Antagonists of MCP-1 function and methods of use thereof

ABSTRACT

Chemical compounds which are antagonists of Monocyte Chemoattractant Protein-1 (MCP-1) function, pharmaceutical compositions comprising these compounds, methods of treatment employing these compounds and compositions, and processes for preparing these compounds. The compounds are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn&#39;s disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 10/106,881,filed 25 Mar. 2002 now U.S. Pat. No. 6,677,365, which claims thepriority under 35 USC 119(e) of U.S. Provisional Application No.60/281,274, filed 3 Apr. 2001. The entire contents of both of thoseapplications are incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to chemical compounds, pharmaceuticalcompositions comprising said compounds, uses of said compounds andcompositions, methods of treatment employing said compounds andcompositions, and processes for preparing said compounds. Specifically,this invention relates to novel compounds which are antagonists ofMonocyte Chemoattractant Protein-1 (MCP-1) function and are useful inthe prevention or treatment of chronic or acute inflammatory orautoimmune diseases, especially those associated with aberrantlymphocyte or monocyte accumulation such as arthritis, asthma,atherosclerosis, diabetic nephropathy, inflammatory bowel disease,Crohn's disease, multiple sclerosis, nephritis, pancreatitis, pulmonaryfibrosis, psoriasis, restenosis, and transplant rejection. Morespecifically, the invention is related to pharmaceutical compositionscomprising these compounds and the use of these compounds andcompositions in the prevention or treatment of such diseases.

BACKGROUND OF THE INVENTION

Chemokines: Structure and Function

The migration of leukocytes from blood vessels into diseased tissues isan important process in the initiation of normal inflammatory responsesto certain stimuli or insults to the immune system. However, thisprocess is also involved in the onset and progression oflife-threatening inflammatory and autoimmune diseases; blockingleukocyte recruitment in these disease states, therefore, can be aneffective therapeutic strategy.

The mechanism by which leukocytes leave the bloodstream and accumulateat inflammatory sites involves three distinct steps: (1) rolling, (2)arrest and firm adhesion, and (3) transendothelial migration [Springer,Nature 346:425–433 (1990); Lawrence and Springer, Cell 65:859–873(1991); Butcher, Cell 67:1033–1036 (1991)]. The second step is mediatedat the molecular level by chemoattractant receptors on the surface ofleukocytes which bind chemoattractant cytokines secreted byproinflammatory cells at the site of damage or infection. Receptorbinding activates leukocytes, increases their adhesiveness to theendothelium, and promotes their transmigration into the affected tissue,where they can secrete inflammatory and chemoattractant cytokines anddegradative proteases that act on the subendothelial matrix,facilitating the migration of additional leukocytes to the site ofinjury.

The chemoattractant cytokines, collectively known as “chemokines,” are alarge family of low molecular weight (8 to 10 kD) proteins that sharethe ability to stimulate directed cell migration (“chemotaxis”) [Schall,Cytokine 3:165–183 (1991); Murphy, Rev Immun 12:593–633 (1994)].

Chemokines are characterized by the presence of four conserved cysteineresidues and are grouped into two main subfamilies based on whether thetwo amino-terminal cysteines are separated by one amino acid (CXCsubfamily, also known as α-chemokines) or immediately adjacent to eachother (CC subfamily, also referred to as β-chemokines) [Baggiolini etal., Adv Immunol 55:97–179 (1994); Baggiolini et al., Annu Rev Immunol15:675–705 (1997); Deng et al., Nature 381:661–666 (1996); Luster, NewEngl J Med 338:436445 (1998); Saunders and Tarby, Drug Discovery Today4:80–92 (1999)].

The chemokines of the CXC subfamily, represented by IL-8, are producedby a wide range of cells and act predominantly on neutrophils asmediators of acute inflammation. The CC chemokines, which include MCP-1,RANTES, MIP-1α, and MIP-1β, are also produced by a variety of cells, butthese molecules act mainly on monocytes and lymphocytes in chronicinflammation.

Like many cytokines and growth factors, chemokines utilize both high andlow affinity interactions to elicit full biological activity. Studiesperformed with labeled ligands have identified chemokine binding sites(“receptors”) on the surface of neutrophils, monocytes, T cells, andeosinophils with affinities in the 500 pM to 10 nM range [Kelvin et al.,J Leukoc Biol 54:604–612 (1993); Murphy, Annu Rev Immunol 12:593–633(1994); Raport et al., J Leukoc Biol 59:18–23 (1996); Premack andSchall, Nature Med 2:1174–1178 (1996)]. The cloning of these receptorshas revealed that cell surface high-affinity chemokine receptors belongto the seven transmembrane (“serpentine”) G-protein-coupled receptor(GPCR) superfamily.

Chemokine receptors are expressed on different cell types, includingnon-leukocyte cells. Some receptors are restricted to certain cells(e.g., the CXCR1 receptor is predominantly restricted to neutrophils),whereas others are more widely expressed (e.g., the CCR2 receptor isexpressed on monocytes, T cells, natural killer cells, dendritic cells,and basophils).

Given that at least twice as many chemokines have been reported to dateas there are receptors, there is a high degree of redundancy in theligands and, not surprisingly, most chemokine receptors are ratherpromiscuous with regard to their binding partners. For example, bothMIP-1α and RANTES bind to the CCR1 and CCR5 receptors, while IL-8 bindsto the CXCR1 and CXCR2 receptors. Although most chemokines receptorsbind more than one chemokine, CC receptors bind only CC chemokines, andCXC receptors bind only CXC chemokines. This ligand-receptor restrictionmay be related to the structural differences between CC and CXCchemokines, which have similar primary, secondary, and tertiarystructures, but different quaternary structures [Lodi et al., Science263:1762–1767 (1994)].

The binding of chemokines to their serpentine receptors is transducedinto a variety of biochemical and physiological changes, includinginhibition of cAMP synthesis, stimulation of cytosolic calcium influx,upregulation or activation of adhesion proteins, receptordesensitization and internalization, and cytoskeletal rearrangementsleading to chemotaxis [Vaddi et al., J Immunol 153:4721–4732 (1994);Szabo et al., Eur J Immunol 27:1061–1068 (1997); Campbell et al.,Science 279:381–384 (1998); Aragay et al., Proc Natl Acad Sci USA95:2985–2990 (1998); Franci et al., J Immunol 157:5606–5612 (1996);Aramori et al., EMBO J 16:4606–4616 (1997); Haribabu et al., J Biol Chem272:28726–28731 (1997); Newton et al., Methods Enzymol 287:174–186(1997)]. In the case of macrophages and neutrophils, chemokine bindingalso triggers cellular activation, resulting in lysozomal enzyme releaseand generation of toxic products from the respiratory burst [Newton etal., Methods Enzymol 287:174–186 (1997); Zachariae et al., J Exp Med171:2177–2182 (1990); Vaddi et al., J Leukocyte Biol 55:756–762 (1994)].The molecular details of the chemokine-receptor interactions responsiblefor inducing signal transduction, as well as the specific pathways thatlink binding to the above mentioned physiological changes, are stillbeing elucidated. Notwithstanding the complexity of these events, it hasbeen shown that in the case of the MCP-1/CCR2 interaction, specificmolecular features of MCP-1 can induce different conformations in CCR2that are coupled to separate post-receptor pathways [Jarnagin et al.,Biochemistry 38:16167–16177 (1999)]. Thus, it should be possible toidentify ligands that inhibit chemotaxis without affecting othersignaling events.

In addition to their high-affinity seven transmembrane GPCRs, chemokinesof both subfamilies bind to various extracellular matrix proteins suchas the glycosaminoglycans (GAGs) heparin, chondroitin sulfate, heparansulfate, and dermatan sulfate with affinities in the middle nanomolar tomillimolar range. These low-affinity chemokine-GAG interactions arebelieved to be critical not only for conformational activation of theligands and presentation to their high-affinity serpentine receptors,but also for the induction of stable chemokine gradients that mayfunction to stimulate haptotaxis (i.e., the migration of specific cellsubtypes in response to a ligand gradient that is affixed upon thesurface of endothelial cells or embedded within the extracellularmatrix) [Witt and Lander, Curr Biol 4:394–400 (1994); Rot, Eur J Immunol23:303–306 (1993); Webb et al., Proc Natl Acad Sci USA 90:7158–7162(1993); Tanaka et al, Nature 361:79–82 (1993); Gilat et al., J Immunol153:4899–4906 (1994)]. Similar ligand-GAG interactions have beendescribed for a variety of cytokines and growth factors, including thevarious members of the FGF family, hepatocyte growth factor, IL-3 andIL-7, GM-CSF, and VEGF [Roberts et al., Nature 332:376–378 (1988); Gilatet al., Immunol Today 17:16–20 (1996); Clarke et al., Cytokine 7:325–330(1995); Miao et al., J Biol Chem 271:4879–4886 (1996); Vlodavsky et al.,Cancer Metastasis Rev 15:177–186 (1996)].

MCP-1 and Diseases

Chemokines have been implicated as important mediators of allergic,inflammatory and autoimmune disorders and diseases, such as asthma,atherosclerosis, glomerulonephritis, pancreatitis, restenosis,rheumatoid arthritis, diabetic nephropathy, pulmonary fibrosis, multiplesclerosis, and transplant rejection. Accordingly, it has been postulatedthat the use of antagonists of chemokine function may help reverse orhalt the progression of these disorders and diseases.

In particular, elevated expression of MCP-1 has been observed in anumber of chronic inflammatory diseases [Proost et al., Int J Clin LabRes 26:211–223 (1996); Taub, D. D. Cytokine Growth Factor Rev 7:355–376(1996)] including, but not limited to, rheumatoid arthritis [Robinson etal., Clin Exp Immunol 101:398–407 (1995); Hosaka et al., ibid.97:451–457 (1994); Koch et al., J Clin Invest 90:772–779 (1992);Villiger et al., J Immunol 149:722–727 (1992)], asthma [Hsieh et al., JAllergy Clin Immunol 98:580–587 (1996); Alam et al., Am J Respir CritCare Med 153:1398–1404 (1996); Kurashima et al., J Leukocyte Biol59:313–316 (1996); Sugiyama et al., Eur Respir J 8:1084–1090 (1995)],and atherosclerosis [Yla-Herttuala et al., Proc Natl Acad Sci USA88:5252–5256 (1991); Nelken et al., J Clin Invest 88:1121–1127 (1991)].

MCP-1 appears to play a significant role during the early stages ofallergic responses because of its ability to induce mast cell activationand LTC4 release into the airway, which directly induces AHR (airwayshyper-responsiveness) [Campbell et al., J Immunol 163:2160–2167 (1999)].

MCP-1 has been found in the lungs of patients with idiopathic pulmonaryfibrosis and is thought to be responsible for the influx of mononuclearphagocytes and the production of growth factors that stimulatemesenchymal cells and subsequent fibrosis [Antoniades et al., Proc NatlAcad Sci USA 89:5371–5375 (1992)]. In addition, MCP-1 is also involvedin the accumulation of monocytes in pleural effusions which isassociated with both Mycobacterium tuberculosis infection and malignancy[Strieter et al., J Lab Clin Med 123:183–197 (1994)].

MCP-1 has also been shown to be constitutively expressed by synovialfibroblasts from rheumatoid arthritis patients, and its levels arehigher in rheumatoid arthritis joints compared to normal joints or thosefrom other arthritic diseases [Koch et al., J Clin Invest 90:772–779(1992)]. These elevated levels of MCP-1 are probably responsible for themonocyte infiltration into the synovial tissue. Increased levels ofsynovial MIP-1α and RANTES have also been detected in patients withrheumatoid arthritis [Kundel et al., J Leukocyte Biol 59:6–12 (1996)].

MCP-1 also plays a critical role in the initiation and development ofatherosclerotic lesions. MCP-1 is responsible for the recruitment ofmonocytes into atherosclerotic areas, as shown by immunohistochemistryof macrophage-rich arterial wall [Yla-Herttuala et al., Proc Natl AcadSci USA 88:5252–5256 (1991); Nelken et al., J Clin Invest 88:1121–1127(1991)] and anti-MCP-1 antibody detection [Takeya et al., Human Pathol24:534–539 (1993)]. LDL-receptor/MCP-1-deficient andapoB-transgenic/MCP-1-deficient mice show significantly less lipiddeposition and macrophage accumulation throughout their aortas comparedwith wild-type MCP-1 strains [Alcami et al., J Immunol 160:624–633(1998); Gosling et al., J Clin Invest 103:773–778 (1999); Gu et al.,Mol. Cell. 2:275–281 (1998); Boring et al., Nature 394:894–897 (1998).

Other inflammatory diseases marked by specific site elevations of MCP-1include multiple sclerosis (MS), glomerulonephritis, and stroke.

These findings suggest that the discovery of compounds that block MCP-1activity would be beneficial in treating inflammatory diseases.

Antagonists of Chemokine Function

Most chemokine antagonists reported to date are either neutralizingantibodies to specific chemokines or receptor-ligand antagonists, thatis, agents that compete with specific chemokines for binding to theircognate serpentine receptors but, unlike the chemokines themselves, donot activate these receptors towards eliciting a functional response[Howard et al., Trend Biotechnol 14:46–51 (1996)].

The use of specific anti-chemokine antibodies has been shown to curtailinflammation in a number of animal models (e.g., anti-MIP-1α inbleomycin-induced pulmonary fibrosis [Smith et al., Leukocyte Biol57:782–787 (1994)]; anti-IL-8 in reperfusion injury [Sekido et al.,Nature 365:654–657 (1995)], and anti-MCP-1 in a rat model ofglomerulonephritis [Wada et al., FASE B J 10:1418–1425 (1996)]). In theMRL-lpr mouse arthritis model, administration of an MCP-1 antagonistsignificantly reduced the overall histopathological score after theearly onset of the disease [Gong et al., J Exp Med 186:131–137 (1997)].

A major problem associated with using antibodies to antagonize chemokinefunction is that they must be humanized before use in chronic humandiseases. Furthermore, the ability of multiple chemokines to bind andactivate a single receptor forces the development of a multiple antibodystrategy or the use of cross-reactive antibodies in order to completelyblock or prevent pathological conditions.

Several small molecule antagonists of chemokine receptor function havebeen reported in the scientific and patent literature [White, J. BiolChem 273:10095–10098 (1998); Hesselgesser, J. Biol Chem 273:15687–15692(1998); Bright et al., Bioorg Med Chem Lett 8:771–774 (1998); Lapierre,26th Natl Med Chem Symposium, June 14–18, Richmond (Va.), USA (1998);Forbes et al., Bioorg Med Chem Lett 10:1803–18064 (2000); Kato et al.,WO Patent 97/24325; Shiota et al., WO Patent 97/44329; Naya et al., WOPatent 98/04554; Takeda Industries, JP Patent 0955572 (1998); Schwenderet al., WO Patent 98/02151; Hagmann et al., WO Patent 98/27815; Connoret al., WO Patent 98/06703; Wellington et al., U.S. Pat. No. 6,288,103B1 (2001)].

The specificity of the chemokine receptor antagonists, however, suggeststhat inflammatory disorders characterized by multiple or redundantchemokine expression profiles will be relatively more refractory totreatment by these agents.

A different approach to target chemokine function would involve the useof compounds that disrupt the chemokine-GAG interaction. One class ofsuch agents with potential therapeutic application would consist ofsmall organic molecules that bind to the chemokine low affinityGAG-binding domain.

Compounds of this class might not inhibit binding of the chemokine toits high-affinity receptor per se, but would disrupt chemokinelocalization within the extracellular matrix and provide an effectiveblock for directed leukocyte-taxis within tissues. An advantage of thisstrategy is the fact that most CC and CXC chemokines possess similarC-terminal protein folding domains that define the GAG-binding site,and, hence, such compounds would be more useful for the treatment ofinflammatory disorders induced by multiple, functionally redundantchemokines [McFadden and Kelvin, Biochem Pharmacol 54:1271–1280 (1997)].

The use of small molecule drugs to bind cytokine ligands and disruptinteractions with extracellular GAGs has been reported withFGF-dependent angiogenesis [Folkman and Shing, Adv Exp Med Biol313:355–364 (1992)]. For example, the heparinoids suramin and pentosanpolysulphate both inhibit angiogenesis under conditions where heparin iseither ineffective or even stimulatory [Wellstein and Czubayko, BreastCancer Res Treat 38:109–119 (1996)]. In the case of suramin, theanti-angiogenic capacity of the drug has also been shown to be targetedagainst VEGF [Waltenberger et al., J Mol Cell Cardiol 28:1523–1529(1996)] which, like FGF, possesses heparin-binding domains similar tothose of the chemokines. Heparin or heparin sulphate has also been shownto directly compete for GAG interactions critical for T-cell adhesionmediated by MIP-1β in vitro [Tanaka et al., Nature 361:79–82 (1993)].

The entire disclosure of all documents cited throughout this applicationare incorporated herein by reference.

SUMMARY OF THE INVENTION

The present invention relates to compounds that inhibit MCP-1-inducedchemotaxis of human monocytic cells both in vitro and in vivo. Thesenovel MCP-1 antagonists are useful for the treatment of inflammatorydiseases, especially those associated with lymphocyte and/or monocyteaccumulation, such as atherosclerosis, diabetic nephropathy,inflammatory bowel disease, Crohn's disease, multiple sclerosis,nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis,rheumatoid arthritis, and other chronic or acute autoimmune disorders.In addition, these compounds can be used in the treatment of allergichypersensitivity disorders, such as asthma and allergic rhinitis,characterized by basophil activation and eosinophil recruitment.

A first embodiment of the present invention provides compounds ofFormula I, Formula II, and Formula III:

where:

-   (A) In Formula I:    -   each of W, X and Y is independently selected from CR⁶R⁷, N—R⁷,        O, or S provided that at least one of W, X and Y is a non-carbon        ring atom, and at least one of W, X and Y is a carbon ring atom.-   (B) In Formula II:    -   W and X are independently selected from C—R⁶ and N, and Y is        selected from CR⁶R⁷, N—R⁷, O, or S, provided that:    -   (i) at least one of W, X, and Y is a non-carbon ring atom, and    -   (ii) when W is C—R⁶ and X is N, then Y is CR⁶R⁷.-   (C) In Formula III:    -   W is selected from CR⁶R⁷, N—R⁷, O, or S, and X and Y are        independently selected from C—R⁶ and N, provided that:    -   (i) at least one of W, X, and Y is a non-carbon ring atom, and    -   (ii) when X is N and Y is C—R⁶, then W is CR⁶R⁷;        and where:

Z is N or C—R⁸;

each R¹, R², R⁶, and R⁸ is independently, hydrogen, optionallysubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(loweralkyl), optionally substituted heterocycloalkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedaryl(lower alkyl), halo(lower alkyl), —CF₃, halogen, nitro, —CN, —OR⁹,—SR⁹, —NR⁹R¹⁰, —NR⁹(carboxy(lower alkyl)), —C(═O)R⁹, —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —SO₂R⁹, —OSO₂R⁹, —SO₂NR⁹R¹⁰, —NR⁹SO₂R¹⁰ or—NR⁹C(═O)R¹⁰, where R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl,optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionallysubstituted aryl, optionally substituted heteroaryl, heteroaryl(loweralkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆— optionally interrupted byone O, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl))or N-(optionally substituted C₁₋₂ alkyl) group,

R³ and R⁴ are independently, hydrogen, lower alkyl, optionallysubstituted lower alkyl, optionally substituted aryl, or optionallysubstituted aryl(lower alkyl), or, together, are —(CH₂)₂₋₄—,

R⁵ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedaryl(lower alkyl), optionally substituted heteroaryl, optionallysubstituted heteroaryl(lower alkyl), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —SO₂R¹¹, or —SO₂NR¹¹R¹², where R¹¹ and R¹² areindependently, hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), aryl, optionallysubstituted heteroaryl, heteroaryl(lower alkyl), or R¹¹ and R¹² togetherare —(CH₂)₄₋₆—,

each R⁷ is hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), —C(═O)R⁹,—C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂NR⁹R¹⁰, where R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl,cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(loweralkyl), aryl(lower alkyl), optionally substituted aryl, optionallysubstituted heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ togetherare —(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group,

or the pharmaceutically acceptable salts thereof, optionally in the formof single stereoisomers or mixtures of stereoisomers thereof.

The compounds of this invention may possess one or more chiral centers,and can therefore be produced as individual stereoisomers or as mixturesof stereoisomers, depending on whether individual stereoisomers ormixtures of stereoisomers of the starting materials are used. Inaddition, some of the compounds of the invention are capable of furtherforming pharmaceutically acceptable salts and esters. The compounds ofthis invention may further exist in tautomeric forms and can thereforebe produced as individual tautomeric forms or as mixtures of tautomericforms. Unless indicated otherwise, the description or naming of acompound or groups of compounds is intended to include both theindividual isomers or mixtures (racemic or otherwise) of stereoisomersand their tautomeric forms. Methods for the determination ofstereochemistry and the separation of stereoisomers are well known to aperson of ordinary skill in the art [see the discussion in Chapter 4 ofMarch J.: Advanced Organic Chemistry, 4th ed. John Wiley and Sons, NewYork, N.Y., 1992]. All of these stereoisomers and pharmaceutical formsare intended to be included within the scope of the present invention.

A second embodiment of the present invention provides compounds ofFormula Ia, Formula IIa, and Formula IIIa:

where:

-   (A) In Formula Ia:    -   each of W, X and Y is independently selected from CR⁶R⁷, N—R⁷,        O, or S provided that at least one of W, X, and Y is a        non-carbon ring atom, and at least one of W, X, and Y is a        carbon ring atom.-   (B) In Formula IIa:    -   W and X are independently selected from C—R⁶ and N, and Y is        selected from CR⁶R⁷, N—R⁷, O, or S, provided that:    -   (i) at least one of W, X, and Y is a non-carbon ring atom, and    -   (ii) when W is C—R⁶ and X is N, then Y is CR⁶R⁷.-   (C) In Formula IIIa:    -   W is selected from CR⁶R⁷, N—R⁷, O, or S, and X and Y are        independently selected from C—R⁶ and N, provided that:    -   (i) at least one of W, X, and Y is a non-carbon ring atom, and    -   (ii) when X is N and Y is C—R⁶, then W is CR⁶R⁷;        and where:

Z is N or C—R⁸;

R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as defined in the first embodiment,

R¹³ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), heterocycloalkyl, optionallysubstituted aryl, optionally substituted aryl(lower alkyl), optionallysubstituted heteroaryl, optionally substituted heteroaryl(lower alkyl),halo(lower alkyl), —CF₃, halo(lower alkyl), halogen, nitro, —CN, —OR¹⁵,—SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵, —C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵,—SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, —NR¹⁵SO₂R¹⁶ or —NR¹⁵C(═O)R¹⁶, where R¹⁵ and R¹⁶are independently, hydrogen, optionally substituted lower alkyl,alkenyl, alkynyl, —CF₃, cycloalkyl, optionally substitutedheterocycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆— optionallyinterrupted by one O, S, NH or N—(C₁₋₂ alkyl) group,

each R¹⁴ is independently selected from optionally substituted loweralkyl, optionally substituted aryl, optionally substituted heteroaryl,hydroxy, halogen, —CF₃, —OR¹⁷, —NR¹⁷R¹⁸, —C(═O)R¹⁷, —C(═O)OR¹⁷,—O(CH₂)_(m)C(═O)OR¹⁷, where m is an integer of 1 to 4, or —C(═O)NR¹⁷R¹⁸,where R¹⁷ and R¹⁸ are independently, hydrogen, lower alkyl, alkenyl,alkynyl, —CF₃, optionally substituted heterocycloalkyl, cycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, heteroaryl,heteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆—, optionallyinterrupted by one O, S, NH or N—(C₁₋₂ alkyl) group, and

n is an integer of 0 to 4,

or the pharmaceutically acceptable salts thereof, optionally in the formof single stereoisomers or mixtures of stereoisomers thereof.

Within this invention, certain compounds are preferred. Such preferredcompounds are:

-   1. compounds of Formula I or Ia where W and Y are O, X is CR⁶R⁷,    where R⁶ and R⁷ are independently hydrogen, lower alkyl, or    optionally substituted aryl, and Z is C—H; or-   2. compounds of Formula II or IIa where W is N, X is CR⁶, where R⁶    is hydrogen, lower alkyl, or optionally substituted aryl, Y is O,    and Z is C—H; or-   3. compounds of Formula III or IIIa where W is O, X is CR⁶, where R⁶    is hydrogen, lower alkyl, or optionally substituted aryl, Y is N,    and Z is C—H; or-   4. compounds of Formula III or IIIa where W is N—R⁷, where R⁷ is    hydrogen, lower alkyl, substituted lower alkyl, or optionally    substituted aryl(lower alkyl), X and Y are each CR⁶, where R⁶ is    hydrogen, lower alkyl, or optionally substituted aryl, and Z is C—H;    or-   5. compounds of Formula II or IIa where W and X are each CR⁶, where    R⁶ is hydrogen, lower alkyl, or optionally substituted aryl, Y is    N—R⁷, where R⁷ is hydrogen, lower alkyl, substituted lower alkyl, or    optionally substituted aryl(lower alkyl), and Z is C—H; or-   6. compounds of Formula II or IIa, where W and X are each N, Y is    N—R⁷, where R⁷ is hydrogen, lower alkyl, substituted lower alkyl, or    optionally substituted aryl(lower alkyl), and Z is C—H; or-   7. compounds of Formula I or Ia where W and X are each CR⁶R⁷, where    R⁶ and R⁷ are independently hydrogen, lower alkyl, or optionally    substituted aryl, Y is O, and Z is C—H; or-   8. compounds of Formula I or Ia, where W is O, X and Y are each    CR⁶R⁷, where R⁶ and R⁷ are independently hydrogen, lower alkyl, or    optionally substituted aryl, and Z is C—H; or-   9. compounds of Formula II or IIa where W is N, X is CR⁶, where R⁶    is hydrogen, lower alkyl, or optionally substituted aryl, Y is N—R⁷,    where R⁷ is hydrogen, lower alkyl, substituted lower alkyl, or    optionally substituted aryl(lower alkyl), and Z is C—H; or-   10. compounds of Formula III or IIIa where W is N—R⁷, where R⁷ is    hydrogen, lower alkyl, substituted lower alkyl, or optionally    substituted aryl(lower alkyl), X is CR⁶, where R⁶ is hydrogen, lower    alkyl, or optionally substituted aryl, Y is N, and Z is C—H; or-   11. compounds of Formula III or IIIa where W is N—R⁷, where R⁷ is    hydrogen, lower alkyl, substituted lower alkyl, or optionally    substituted aryl(lower alkyl), X and Y are each N, and Z is C—H; or-   12. compounds of the first and second embodiments where R¹ and R²    are independently selected from hydrogen, lower alkyl, halogen,    optionally lower alkyl substituted heterocycloalkyl, —OR⁹, —SR⁹, or    —NR⁹R¹⁰, where R⁹ and R¹⁰ are hydrogen, lower alkyl or optionally    substituted aryl; and/or-   13. compounds of the first and second embodiments where R³ and R⁴    are independently selected from hydrogen or lower alkyl; or-   14. compounds of Formula I or Ia where W and X are each CR⁶R⁷, where    R⁶ and R⁷ are independently hydrogen, lower alkyl, or optionally    substituted aryl, and Z is N—R⁷; or-   15. compounds of Formula I or Ia where W is CR⁶R⁷, where R⁶ and R⁷    are independently hydrogen, lower alkyl, or optionally substituted    aryl, X is O, and Z is N—R⁷; or-   16. compounds of Formula I or Ia where W is O, X is CR⁶R⁷, where R⁶    and R⁷ are independently hydrogen, lower alkyl, or optionally    substituted aryl, and Z is N—R⁷.

Compounds of the second embodiment are preferred. Within the secondembodiment, preferred compounds are those where:

-   1. R¹³ is independently selected from optionally substituted aryl,    optionally substituted heteroaryl, halogen, —CF₃, —CN, —OR¹⁵,    —C(═O)R¹⁵, —C(═O)OR¹⁵, or —C(═O)NR¹⁵R¹⁶, where R¹⁵ and R¹⁶ are    independently, hydrogen, lower alkyl, halo(lower alkyl), optionally    substituted aryl, optionally substituted heteroaryl,    heteroaryl(lower alkyl) or R¹⁵ and R¹⁶ together are —(CH₂)₄₋₆—,    optionally interrupted by one O, S, NH or N—(C₁₋₂ alkyl) group, such    as piperazinyl, 4-methylpiperazin-1-yl, morpholyl,    hexahydropyrimidyl, and the like; and/or-   2. each R¹⁴ is independently selected from halogen, —CF₃, —OR¹⁷,    —C(═O)OR¹⁷, —O(CH₂)_(m)C(═O)OR¹⁷, where m is an integer of 1 to 4,    or —C(═O)NR¹⁷R¹⁸, where R¹⁷ and R¹⁸ are independently, hydrogen,    lower alkyl, optionally substituted aryl, heteroaryl, or    heteroaryl(lower alkyl), or R¹⁷ and R¹⁸ together are —(CH₂)₄₋₆—,    optionally interrupted by one O, S, NH or N—(C₁₋₂ alkyl) group, such    as piperazinyl, 4-methylpiperazin-1-yl, morpholyl, and the like.

A number of different preferences have been given above, and followingany one of these preferences results in a compound of this inventionthat is more presently preferred than a compound in which thatparticular preference is not followed. However, these preferences aregenerally independent [although preferences 1–11 above are mutuallyexclusive], and additive; and following more than one of thesepreferences may result in a more presently preferred compound than onein which fewer of the preferences are followed.

A third embodiment of the present invention provides pharmaceuticalcompositions comprising a pharmaceutically acceptable excipient and atherapeutically effective amount of at least one compound of thisinvention.

A fourth embodiment of the present invention provides methods fortreating diseases treatable by administration of an MCP-1 inhibitor, forexample, chronic or acute inflammatory or autoimmune diseases such asasthma, atherosclerosis, diabetic nephropathy, glomerulonephritis,inflammatory bowel disease, Crohn's disease, multiple sclerosis,pancreatitis, pulmonary fibrosis, psoriasis, restenosis, rheumatoidarthritis, or a transplant rejection in mammals in need thereof,comprising the administration to such mammal of a therapeuticallyeffective amount of at least one compound of this invention or apharmaceutically acceptable salt thereof or a pharmaceutical compositioncomprising the same.

A fifth embodiment of this invention provides processes for thepreparation of the compounds of the invention and the pharmaceuticallyacceptable salts thereof.

A sixth embodiment of this invention provides uses of the compounds ofthe invention in the preparation of medicaments for the treatment ofchronic or acute inflammatory or autoimmune diseases such as asthma,atherosclerosis, diabetic nephropathy, glomerulonephritis, inflammatorybowel disease, Crohn's disease, multiple sclerosis, pancreatitis,pulmonary fibrosis, psoriasis, restenosis, rheumatoid arthritis, or atransplant rejection.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and General Parameters

The following definitions apply to the description of compounds of thepresent invention:

“Alkyl” is a linear or branched saturated hydrocarbon radical havingfrom 1 to 20 carbon atoms. Examples of alkyl radicals are: methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, n-hexyl, dodecyl, etc.

“Lower alkyl”, as in “lower alkyl,” “lower alkoxy,” “cycloalkyl(loweralkyl),” “aryl(lower alkyl)”, or “heteroaryl(lower alkyl)”, means aC₁₋₁₀ alkyl radical. Preferred lower alkyl radicals are those havingfrom 1 to 6 carbon atoms.

“Alkenyl” is a linear or branched hydrocarbon radical having from 2 to20 carbon atoms and at least one carbon-carbon double bond. Examples ofalkenyl radicals are: vinyl, 1-propenyl, isobutenyl, etc.

“Alkynyl” is a linear or branched hydrocarbon radical having from 2 to20 carbon atoms and at least one carbon-carbon triple bond. Examples ofalkynyl radicals are: propargyl, 1-butynyl, etc.

“Cycloalkyl” is a monovalent cyclic hydrocarbon radical having from 3 to12 carbon atoms. Examples of cycloalkyl radicals are: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc.

“Substituted cycloalkyl” is a monovalent cyclic hydrocarbon radicalhaving from 3 to 12 carbon atoms, which is substituted with one, two, orthree substituents each independently selected from aryl, substitutedaryl, heteroaryl, halogen, —CF₃, nitro, —CN, —OR, —SR, —NRR′, —C(═O)R,—OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′, —C(═O)NRR′,—NRC(═O)R′ or —PO₃HR, where R and R′ are, independently, hydrogen, loweralkyl, cycloalkyl, aryl, substituted aryl, aryl(lower alkyl),substituted aryl(lower alkyl), heteroaryl, or heteroaryl(lower alkyl),and having 3 to 12 ring atoms, 1 to 5 of which are heteroatoms chosen,independently, from N, O, or S, and includes monocyclic, condensedheterocyclic, and condensed carbocyclic and heterocyclic rings (e.g.,piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl,perhydropyrrolizinyl, 1,4-diazaperhydroepinyl[perhydro-1,4-diazepinyl],etc.).

“Cycloalkyl(lower alkyl)” is a lower alkyl radical which is substitutedwith a cycloalkyl, as previously defined. Examples of cycloalkyl(loweralkyl) radicals are cyclopropylmethyl, cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, etc.

“Heterocycloalkyl” is a monovalent cyclic hydrocarbon radical having 3to 12 carbon ring atoms, 1 to 5 of which are heteroatoms chosen,independently, from N, O, or S, and includes monocyclic, condensedheterocyclic, and condensed carbocyclic and heterocyclic rings (e.g.,piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl,perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, etc.).

“Substituted heterocycloalkyl” is a monovalent cyclic hydrocarbonradical having from 3 to 12 carbon atoms, which is substituted with one,two, or three substituents each independently selected from aryl,substituted aryl, heteroaryl, halogen, —CF₃, nitro, —CN, —OR, —SR,—NRR′, —C(═O)R, —OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′,—C(═O)NRR′, —NRC(═O)R′ or —PO₃HR, where R and R′ are, independently,hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl, aryl(loweralkyl), substituted aryl(lower alkyl), heteroaryl, or heteroaryl(loweralkyl), and having 3 to 12 ring atoms, 1 to 5 of which are heteroatomschosen, independently, from N, O, or S, and includes monocyclic,condensed heterocyclic, and condensed carbocyclic and heterocyclic rings(e.g., piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl,perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, etc.).

“Substituted heterocycloalkyl(lower alkyl)” is a lower alkyl radicalwhich is substituted with a monovalent cyclic hydrocarbon radical havingfrom 3 to 12 carbon atoms, which is substituted with one, two, or threesubstituents each independently selected from aryl, substituted aryl,heteroaryl, halogen, —CF₃, nitro, —CN, —OR, —SR, —NRR′, —C(═O)R,—OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′, —C(═O)NRR′,—NRC(═O)R′ or —PO₃HR, where R and R′ are, independently, hydrogen, loweralkyl, cycloalkyl, aryl, substituted aryl, aryl(lower alkyl),substituted aryl(lower alkyl), heteroaryl, or heteroaryl(lower alkyl),and having 3 to 12 ring atoms, 1 to 5 of which are heteroatoms chosen,independently, from N, O, or S, and includes monocyclic, condensedheterocyclic, and condensed carbocyclic and heterocyclic rings (e.g.,piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl,perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, etc.).

“Substituted alkyl” or “substituted lower alkyl,” is an alkyl or loweralkyl radical, respectively, which is substituted with one, two, orthree substituents each independently selected from aryl, substitutedaryl, heteroaryl, halogen, —CF₃, nitro, —CN, —OR, —SR, —NRR′, —C(═O)R,—OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′, —C(═O)NRR′,—NRC(═O)R′, or —PO₃HR, where R and R′ are, independently, hydrogen,lower alkyl, cycloalkyl, aryl, substituted aryl, aryl(lower alkyl),substituted aryl(lower alkyl), heteroaryl, or heteroaryl(lower alkyl).

“Halo(lower alkyl)” is a radical derived from lower alkyl containing atleast one halogen substituent. Non-limiting examples of halo(loweralkyl) radicals include: —CF₃, C₂F₅, etc.

“Aryl”, as in “aryl”, “aryloxy”, and “aryl(lower alkyl)”, is a radicalderived from an aromatic hydrocarbon containing 6 to 16 ring carbonatoms, having a single ring (e.g., phenyl), or two or more condensedrings, preferably 2 to 3 condensed rings (e.g., naphthyl), or two ormore aromatic rings, preferably 2 to 3 aromatic rings, which are linkedby a single bond (e.g., biphenyl). Preferred aryl radicals are thosecontaining from 6 to 14 carbon atoms.

“Substituted aryl” is an aryl radical which is substituted with one,two, or three substituents each independently selected from alkyl,substituted alkyl, halo(lower alkyl), halogen, nitro, —CN, —OR, —SR,—NRR′, —C(═O)R, —OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —PO₃H₂,—NRSO₂R′, —C(═O)NRR′ or —NRC(═O)R′, where R and R′ are, independently,hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, aryl,substituted aryl, optionally substituted aryl(lower alkyl), heteroaryl,or heteroaryl(lower alkyl). Preferred substituted aryl radicals arethose substituted with one, two, or three substituents eachindependently selected from the group consisting of lower alkyl,halogen, —CF₃, nitro, —CN, —OR, —NRR′, —C(═O)NRR′, —SO₂OR, —SO₂NRR′,—PO₃H₂, —NRSO₂R′ or —NRC(═O)R′.

“Heteroaryl”, as in “heteroaryl” and “heteroaryl(lower alkyl)”, is aradical derived from an aromatic hydrocarbon containing 5 to 14 ringatoms, 1 to 5 of which are heteroatoms chosen, independently, from N, O,or S, and includes monocyclic, condensed heterocyclic, and condensedcarbocyclic and heterocyclic aromatic rings (e.g., thienyl, furyl,pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl, isobenzofuranyl,purinyl, isoquinolyl, pteridinyl, imidazolyl, pyridyl, pyrazolyl,pyrazinyl, quinolyl, etc.).

“Substituted heteroaryl” is a heteroaryl radical which is substitutedwith one, two, or three substituents each independently selected fromalkyl, substituted alkyl, halogen, CF₃, nitro, —CN, —OR, —SR, —NRR′,—C(═O)R, OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′,—C(═O)NRR′, or —NRC(═O)R′, where R and R′ are, independently, hydrogen,lower alkyl, substituted lower alkyl, cycloalkyl, aryl, substitutedaryl, aryl(lower alkyl), substituted aryl(lower alkyl), heteroaryl, orheteroaryl(lower alkyl). Particularly preferred substituents on thesubstituted heteroaryl moiety include lower alkyl, substituted loweralkyl, halo(lower alkyl), halogen, nitro, —CN, —OR, —SR, and —NRR′.

“Aryl(lower alkyl)” is a lower alkyl radical which is substituted withan aryl, as previously defined.

“Substituted aryl(lower alkyl)” is an aryl(lower alkyl) radical havingone to three substituents on either or both of the aryl and the alkylportion of the radical.

“Heteroaryl(lower alkyl)” is a lower alkyl radical which is substitutedwith a heteroaryl, as previously defined.

“Substituted heteroaryl(lower alkyl)” is a heteroaryl(lower alkyl)radical having one to three substituents on the heteroaryl portion orthe alkyl portion of the radical, or both.

“Lower alkoxy” is an —OR radical, where R is a lower alkyl orcycloalkyl.

“Halogen” means fluoro, chloro, bromo, or iodo.

“Stereoisomers” are compounds that have the same sequence of covalentbonds and differ in the relative disposition of their atoms in space.

“Inner salts” or “Zwitterions” are compounds where the positive andnegative groups, such as amine and acid groups within the compound, areequally ionized. The compounds are charge separated species that resultfrom the transfer of a proton from the acidic site to a basic site,typically in a compound containing an amine and an acid group.

“Tautomers” are isomeric compounds that differ from one another byinterchanged positions of σ and π bonds. The compounds are inequilibrium with one another. They may also differ from one another inthe position at which a hydrogen atom is attached.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic, and desirable, and includes excipients that are acceptablefor veterinary use as well as for human pharmaceutical use. Suchexcipients may be solid, liquid, semisolid, or, in the case of anaerosol composition, gaseous.

“Pharmaceutically acceptable salts and esters” means any salt and esterthat is pharmaceutically acceptable and has the desired pharmacologicalproperties. Such salts include salts that may be derived from aninorganic or organic acid, or an inorganic or organic base, includingamino acids, which is not toxic or undesirable in anyway. Suitableinorganic salts include those formed with the alkali metals, e.g.,sodium and potassium, magnesium, calcium, and aluminum. Suitable organicsalts include those formed with organic bases such as the amine bases,e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. Such salts also include acid additionsalts formed with inorganic acids (e.g., hydrochloric and hydrobromicacids) and organic acids (e.g., acetic acid, citric acid, maleic acid,and the alkane and arene-sulfonic acids such as methanesulfonic acid andbenzenesulfonic acid). Pharmaceutically acceptable esters include estersformed from carboxy, sulfonyloxy, and phosphonoxy groups present in thecompounds, e.g., C₁₋₆ alkyl esters. When there are two acidic groupspresent, a pharmaceutically acceptable salt or ester may be amono-acid-mono-salt or ester or a di-salt or ester; and similarly, wherethere are more than two acidic groups present, some or all of suchgroups can be salified or esterified.

“Therapeutically effective amount” means that amount which, whenadministered to a mammal for treating a disease, is sufficient to effectsuch treatment for the disease.

“Treating” or “treatment” of a disease in a mammal includes:

-   (1) Preventing the disease from occurring in a mammal which may be    predisposed to the disease but does not yet experience or display    symptoms of the disease;-   (2) Inhibiting the disease, i.e., arresting its development, or-   (3) Relieving the disease, i.e., causing regression of the disease.

“Disease” includes any unhealthy condition of an animal (which includeshuman and non-human mammals), including particularly various forms ofinflammatory illnesses or diseases, such as asthma, atherosclerosis,diabetic nephropathy, glomerulonephritis, inflammatory bowel disease,Crohn's disease, multiple sclerosis, pancreatitis, pulmonary fibrosis,psoriasis, restenosis, rheumatoid arthritis, immune disorders, andtransplant rejection.

The Compounds and Their Pharmaceutically Acceptable Salts

The first embodiment of the present invention provides compounds ofFormula I, Formula II, and Formula III:

where W, X, Y, Z, and R¹ to R⁵ are as defined above,or a pharmaceutically acceptable salt thereof, optionally in the form ofa single stereoisomer or mixture of stereoisomers thereof.

Preferably, R¹ is hydrogen, optionally substituted lower alkyl,cycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aryl(lower alkyl), halogen, —OR⁹, —NR⁹[carboxy(loweralkyl)], —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, where R⁹and R¹⁰ are independently, hydrogen, optionally substituted lower alkyl,lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted heteroaryl,heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)),N-(carboxy(lower alkyl)) or N-(optionally substituted C₁₋₂ alkyl) group.

More preferably, R¹ is optionally substituted lower alkyl, cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halogen, —OR⁹, —NR⁹[carboxy(lower alkyl)], —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, where R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted heteroaryl,heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)),N-(carboxy(lower alkyl)) or N-(optionally substituted C₁₋₂ alkyl) group.

Preferably, R² is hydrogen, optionally substituted lower alkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halo(lower alkyl), halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, or—C(═O)NR⁹R¹⁰, where R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), optionally substitutedcycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted heteroaryl, heteroaryl(lower alkyl), or R⁹ andR¹⁰ together are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH,N-(aryl), N-[aryl(lower alkyl)], N-(carboxy(lower alkyl)) orN-(optionally substituted C₁₋₂ alkyl) group.

More preferably, R² is optionally substituted lower alkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aryl(lower alkyl),halo(lower alkyl), halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, or —C(═O)NR⁹R¹⁰,where R⁹ and R¹⁰ are independently, hydrogen, optionally substitutedlower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionallysubstituted heterocycloalkyl), optionally substituted cycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, heteroaryl,heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH, N-(aryl), N-[aryl(lower alkyl)],N-[carboxy(lower alkyl)] or N-(optionally substituted C₁₋₂ alkyl) group.

Preferably, R³ and R⁴ are independently, hydrogen or lower alkyl, ortogether are —(CH₂)₂₋₄—. More preferably, R³ and R⁴ are independently,hydrogen or lower alkyl.

Preferably, R⁵ is hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedheterocycloalkyl, optionally substituted aryl, aryl(lower alkyl),optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl), halo(lower alkyl), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —SO₂R¹¹, or —SO₂NR¹¹R¹², where R¹¹ and R¹² areindependently, hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), aryl, heteroaryl,heteroaryl(lower alkyl), or R¹¹ and R¹² together are —(CH₂)₄₋₆—.

Preferably, R⁶ and R⁷ are independently hydrogen, optionally substitutedlower alkyl, alkenyl, cycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted aryl(lower alkyl), optionally substituted heteroaryl,optionally substituted heteroaryl(lower alkyl), —C(═O)R⁹, —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂R⁹R¹⁰, where R⁹ and R¹⁰ are independently,hydrogen, optionally substituted lower alkyl, cycloalkyl,cycloalkyl(lower alkyl), aryl, heteroaryl, heteroaryl(lower alkyl), orR⁹ and R¹⁰ together are —(CH₂)₄₋₆—.

More preferably, R⁶ and R⁷ are independently hydrogen, optionallysubstituted lower alkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted aryl(lower alkyl), —C(═O)R⁹, —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂NR⁹R¹⁰, where R⁹ and R¹⁰ are independently,hydrogen, optionally substituted lower alkyl, lower alkyl-N(C₁₋₂alkyl)₂, alkenyl, alkynyl, optionally substituted cycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, heteroaryl, orheteroaryl(lower alkyl).

Preferably, R⁸ is hydrogen, optionally substituted lower alkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halo(lower alkyl), —CF₃, halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)R⁹,—C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —SO₂R⁹, —SO₂NR⁹R¹⁰, —NR⁹SO₂R¹⁰ or—NR⁹C(═O)R¹⁰, where R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, optionallysubstituted cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedaryl, heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.

Where R⁹ and R¹⁰ together are —(CH₂)₄₋₆— optionally interrupted by oneO, S, NH, N-(aryl), N-[aryl(lower alkyl)], N-[carboxy(lower alkyl)] orN-(optionally substituted C₁₋₂ alkyl) group, examples includepiperidinyl, piperazinyl, 4-methylpiperazinyl,4-(carboxymethyl)piperazinyl, 4-morpholyl, and hexahydropyrimidyl.

A particularly preferred “substituted aryl” is a phenyl groupsubstituted with R¹³ and optionally substituted with up to four R¹⁴s,where R¹³ and R¹⁴ are defined with respect to Formulae Ia, IIa and IIIa.

The above-listed preferences equally apply for the compounds of FormulaeIa, IIa, and IIIa below.

In a more preferred version of the first embodiment of the invention,

-   (A) in Formula I;    -   W and X are C—R⁶, Y is O, and Z is C—R⁸, or    -   W and Y are O, and Z is C—R⁸.

In another more preferred version of the first embodiment of theinvention,

-   (B) in Formula II;    -   W is N, Y is O, and Z is C—R⁸, or    -   W and X are C—R⁶, Y is N—R⁷, and Z is C—R⁸, or    -   W and X are N, Y is N—R⁷, and Z is C—R⁸, or    -   W is N and Y is N—R⁷, and Z is C—R⁸.

In another more preferred version of the first embodiment of theinvention,

-   (C) in Formula III;    -   W is N—R⁷, and Z is C—R⁸, or    -   W is O and Y is N, and Z is C—R⁸, or    -   W is N—R⁷, and X and Y are C—R⁶, and Z is C—R⁸.-   For (A), (B) and (C);    -   R¹, R³ and R⁴ are hydrogen, and    -   R⁵ is optionally substituted aryl or optionally substituted        heteroaryl.        or a pharmaceutically acceptable salt thereof, optionally in the        form of a single stereoisomer or mixture of stereoisomers        thereof.

In another more preferred version of the first embodiment of theinvention,

-   -   R² is hydrogen or chlorine,    -   R³ and R⁴ are hydrogen or lower alkyl, and    -   R⁵ is optionally substituted aryl or optionally substituted        heteroaryl,        or a pharmaceutically acceptable salt thereof, optionally in the        form of a single stereoisomer or mixture of stereoisomers        thereof.

The second embodiment of the present invention provides compounds ofFormula Ia, Formula IIa, or Formula IIIa:

where:

-   -   (A) in Formula Ia:    -   each of W, X and Y is independently selected from CR⁶R⁷, N—R⁷,        O, or S provided that at least one of W, X, and Y is a        non-carbon ring atom, and at least one of W, X and Y is a carbon        ring atom;    -   (B) in Formula IIa:    -   W and X are independently selected from C—R⁶ and N, and Y is        selected from CR⁶R⁷, N—R⁷, O, or S, provided that:    -   (i) at least one of W, X, and Y is a non-carbon ring atom, and    -   (ii) when W is C—R⁶ and X is N, then Y is CR⁶R⁷;    -   (C) in Formula IIIa:    -   W is selected from CR⁶R⁷, N—R⁷, O, or S, and X and Y are        independently selected from C—R⁶ and N, provided that:    -   (i) at least one of W, X, and Y is a non-carbon ring atom, and    -   (ii) when X is N and Y is C—R⁶, then W is CR⁶R⁷;        and where:    -   Z is N or C—R⁸;    -   R¹, R², R³, R³, R⁶, R⁷, and R⁸ are as defined in the first        embodiment,

R¹³ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), heterocycloalkyl, optionallysubstituted aryl, optionally substituted aryl(lower alkyl), optionallysubstituted heteroaryl, optionally substituted heteroaryl(lower alkyl),halo(lower alkyl), —CF₃, halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶,—C(═O)R¹⁵, —C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶,—NR¹⁵SO₂R¹⁶ or —NR¹⁵C(═O)R¹⁶, where R¹⁵ and R¹⁶ are independently,hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, —CF₃,cycloalkyl, halo(lower alkyl), optionally substituted heterocycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heteroaryl(lower alkyl)or, together, are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH orN—(C₁₋₂ alkyl) group,

each R¹⁴ is independently selected from optionally substituted loweralkyl, optionally substituted aryl, optionally substituted heteroaryl,hydroxy, halogen, —CF₃, —OR¹⁷, —NR¹⁷R¹⁸, —C(═O)R¹⁷, —C(═O)OR¹⁷,—O(CH₂)_(m)C(═O)OR¹⁷, where m is an integer of 1 to 4, or —C(═O)NR¹⁷R¹⁸,where R¹⁷ and R¹⁸ are independently, hydrogen, lower alkyl, alkenyl,alkynyl, —CF₃, optionally substituted heterocycloalkyl, cycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, heteroaryl,heteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆—, optionallyinterrupted by one O, S, NH or N—(C₁₋₂ alkyl) group, and

n is an integer of 0 to 4,

and the pharmaceutically acceptable salts thereof, optionally in theform of single stereoisomers or mixtures of stereoisomers thereof.

Preferably, R¹, R², and R⁸ are optionally substituted lower alkyl,cycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aryl(lower alkyl), halogen, —OR⁹, —NR⁹[carboxy(loweralkyl)], —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, where R⁹and R¹⁰ are independently, hydrogen, lower alkyl, or R⁹ and R¹⁰ togetherare —(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group,

n is a stereocompatible integer of 0 to 4. The term “stereocompatible”limits the number of substituents permissible by available valences inaccordance with space requirements of the substituents.

Preferably, R¹³ is hydrogen, optionally substituted lower alkyl,alkenyl, heterocycloalkyl, optionally substituted aryl, optionallysubstituted aryl(lower alkyl), optionally substituted heteroaryl,optionally substituted heteroaryl(lower alkyl), halo(lower alkyl), —CF₃,halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵, —C(═O)OR¹⁵,—C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, or —NR¹⁵C(═O)R¹⁶, whereR¹⁵ and R¹⁶ are independently, hydrogen, optionally substituted loweralkyl, alkenyl, cycloalkyl, optionally substituted heterocycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heteroaryl(lower alkyl)or, together, are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH orN—(C₁₋₂ alkyl) group.

More preferably, R¹³ is optionally substituted lower alkyl, alkenyl,heterocycloalkyl, optionally substituted aryl, optionally substitutedaryl(lower alkyl), optionally substituted heteroaryl, optionallysubstituted heteroaryl(lower alkyl), halo(lower alkyl), —CF₃, halogen,nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵, —C(═O)OR¹⁵,—C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, or —NR¹⁵C(═O)R¹⁶, whereR¹⁵ and R¹⁶ are independently, hydrogen, optionally substituted loweralkyl, alkenyl, cycloalkyl, optionally substituted heterocycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heteroaryl(lower alkyl)or, together, are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH orN—(C₁₋₂ alkyl) group.

Preferably, each R¹⁴ is independently selected from optionallysubstituted lower alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, hydroxy, halogen, —CF₃, —OR¹⁷—NR¹⁷R¹⁸,—C(═O)R¹⁸, —C(═O)OR¹⁸, —C(═O)NR¹⁷R¹⁸, where R¹⁷ and R¹⁸ are,independently, hydrogen, lower alkyl, alkenyl, or optionally substitutedaryl.

Preferably, where R¹³ is not hydrogen, n is an integer of 1 to 2. Morepreferably, where R¹³ is not hydrogen, n is 1.

In a more preferred version of the second embodiment of the invention,(A) in Formula Ia;

W and X are C—R⁶, Y is O, and Z is C—R⁸, or

W and Y are O, and Z is C—R⁸,

each R¹³ and R¹⁴ is, independently, lower alkyl, alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, halo(lower alkyl),—CF₃, halogen, nitro, —OR¹⁵, —SR¹⁵, or —C(═O)NR¹⁵R¹⁶, where R¹⁵ and R¹⁶are independently, hydrogen, optionally substituted lower alkyl, or—CF₃, or

W and X are CR⁶R⁷, Y is O, and each R¹³ and R¹⁴ is, independently, —CF₃,halogen, —OR¹⁵, where R¹⁵ is independently, hydrogen, optionallysubstituted lower alkyl, or —CF₃.

In another more preferred version of the second embodiment of theinvention, (B) in Formula IIa;

W is N, Y is O, and Z is C—R⁸, and each R¹³ and R¹⁴ is, independently,—CF₃, halogen, or

W and X are C—R⁶, Y is N—R⁷, Z is C—R⁸, and each R¹³ and R¹⁴ is,independently, —CF₃, or halogen, or

W and X are N, Y is N—R⁸, Z is C—R⁸, and R¹³ and R¹⁴ are halogen, or

W is N and Y is N—R⁷, Z is C—R⁸, and R¹³ and R¹⁴ are halogen.

In another more preferred version of the second embodiment of theinvention, (C) in Formula IIIa;

W is N—R⁷, Z is C—R⁸, and each R¹³ and R¹⁴ is, independently, —CF₃,halogen, or —CN, or

W is O and Y is N, Z is C—R⁸, and each R¹³ and R¹⁴ is, independently,halo(lower alkyl), —CF₃, halogen, nitro, —OR¹⁵, —SR¹⁵, or —CO₂R¹⁵, whereR¹⁵ is hydrogen, or —CF₃, or

W is N—R⁷, and X and Y are C—R⁶, Z is C—R⁸, and each R¹³ and R¹⁴ is,independently, —CF₃, halogen, or —CN.

Most preferably, independently,

-   1. For Formula Ia, W and Y is O, X is CR⁶R⁷, and Z is C—H.-   2. For Formula IIa, W is N, X is C—H, Y is O, and Z is C—H.-   3. For Formula IIa, W and X are C—H, Y is N—CH₃, and Z is C—H.-   4. For Formula IIa, W and X are N, Y is N—H, and Z is C—H.-   5. For Formula IIIa, W is O, X is C—H, Y is N, and Z is C—H.-   6. For Formula IIIa, W is N—CH₃, X is C—H, Y is N—CH₃, and Z is C—H.-   7. R¹, R³ and R⁴ are hydrogen.-   8. R² is hydrogen or chlorine.-   9. R¹³ and R¹⁴ are independently selected from lower all, halogen,    optionally substituted aryl, optionally substituted heteroaryl,    —CF₃, nitro, —OCF₃, —SCF₃, halo(lower alkyl), —CN, —OR¹⁵, —C(═O)R¹⁵,    —C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶, or —CO₂H.

The preferred compounds of the invention are listed in Tables 1–11below.

The compounds of this invention may possess one or more chiral centers,and can therefore exist as individual stereoisomers or as mixtures ofstereoisomers. In such cases, all stereoisomers also fall within thescope of this invention. The compounds of this invention may also existin various tautomeric forms, and in such cases, all tautomers also fallwithin the scope of this invention. The invention compounds include theindividually isolated stereoisomers and tautomers as well as mixtures ofsuch stereoisomers and their tautomers.

Some of the compounds of Formula I, Formula II, and Formula III arecapable of further forming pharmaceutically acceptable salts and esters.All of these forms are included within the scope of the presentinvention.

Pharmaceutically acceptable base addition salts of the compounds ofFormula I, Formula II, and Formula III include salts which may be formedwhen acidic protons present in the parent compound are capable ofreacting with inorganic or organic bases. Typically, the parent compoundis treated with an excess of an alkaline reagent, such as hydroxide,carbonate, or alkoxide, containing an appropriate cation. Cations suchas Na⁺, K⁺, Ca²⁺, and NH₄ ⁺ are examples of cations present inpharmaceutically acceptable salts. The Na⁺ salts are especially useful.Acceptable inorganic bases, therefore, include aluminum hydroxide,calcium hydroxide, potassium hydroxide, sodium carbonate and sodiumhydroxide. Salts may also be prepared using organic bases, such ascholine, dicyclohexylamine, ethylenediamine, ethanolamine,diethanolamine, triethanolamine, procaine, N-methylglucamine, and thelike [for a nonexclusive list see, for example, Berge et al.,“Pharmaceutical Salts,” J. Pharm. Sci. 66:1 (1977)]. The free acid formmay be regenerated by contacting the base addition salt with an acid andisolating the free acid in the conventional manner. The free acid formscan differ from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I, Formula II, and Formula III include salts which may be formedwhen the parent compound contains a basic group. Acid addition salts ofthe compounds are prepared in a suitable solvent from the parentcompound and an excess of a non-toxic inorganic acid, such ashydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfateand bisulfate salts), nitric acid, phosphoric acid and the like, or anon-toxic organic acid such as acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, salicylic acid, p-toluenesulfonic acid, hexanoic acid, heptanoicacid, cyclopentanepropionic acid, lactic acid, o-(4-hydroxy-benzoyl,benzoic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, camphorsulfonic acid,4-methyl-bicyclo[2.2.2.]oct-2-ene-1-carboxylic acid, glucoheptonic acid,gluconic acid, 4,4′-methylenebis(3-hydroxy-2-naphthoic)acid,3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid,laurylsulfuric acid, glucuronic acid, glutamic acid,3-hydroxy-2-naphthoic acid, stearic acid, muconic acid, and the like.The free base form may be regenerated by contacting the acid additionsalt with a base and isolating the free base in the conventional manner.The free base forms can differ from their respective salt forms somewhatin certain physical properties such as solubility in polar solvents.

Also included in the embodiment of the present invention are salts ofamino acids such as arginate and the like, gluconate, and galacturonate[see Berge, supra (1977)].

Some of the compounds of the invention may form inner salts orZwitterions.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms,and are intended to be encompassed within the scope of the presentinvention.

Certain of the compounds of the present invention may also exist in oneor more solid or crystalline phases or polymorphs, the variablebiological activities of such polymorphs or mixtures of such polymorphsare also included in the scope of this invention.

Pharmaceutical Compositions

A third embodiment of the present invention provides pharmaceuticalcompositions comprising pharmaceutically acceptable excipients and atherapeutically effective amount of at least one compound of thisinvention.

Pharmaceutical compositions of the compounds of this invention, orderivatives thereof, may be formulated as solutions or lyophilizedpowders for parenteral administration. Powders may be reconstituted byaddition of a suitable diluent or other pharmaceutically acceptablecarrier prior to use. The liquid formulation is generally a buffered,isotonic, aqueous solution. Examples of suitable diluents are normalisotonic saline solution, 5% dextrose in water or buffered sodium orammonium acetate solution. Such formulations are especially suitable forparenteral administration but may also be used for oral administration.It may be desirable to add excipients such as polyvinylpyrrolidinone,gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodiumchloride, or sodium citrate.

Alternatively, these compounds may be encapsulated, tableted, orprepared in an emulsion or syrup for oral administration.Pharmaceutically acceptable solid or liquid carriers may be added toenhance or stabilize the composition, or to facilitate preparation ofthe composition. Liquid carriers include syrup, peanut oil, olive oil,glycerin, saline, alcohols, or water. Solid carriers include starch,lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate orstearic acid, talc, pectin, acacia, agar, or gelatin. The carrier mayalso include a sustained release material such as glyceryl monostearateor glyceryl distearate, alone or with a wax. The amount of solid carriervaries but, preferably, will be between about 20 mg to about 1 g perdosage unit.

The pharmaceutical preparations are made following the conventionaltechniques of pharmacy involving milling, mixing, granulation, andcompressing, when necessary, for tablet forms; or milling, mixing, andfilling for hard gelatin capsule forms. When a liquid carrier is used,the preparation will be in the form of a syrup, elixir, emulsion, or anaqueous or non-aqueous suspension. Such a liquid formulation may beadministered directly p.o. or filled into a soft gelatin capsule.

Some specific examples of suitable pharmaceutical compositions aredescribed in Examples 7–9.

Typically, a pharmaceutical composition of the present invention ispackaged in a container with a label indicating the use of thepharmaceutical composition in the treatment of a disease such as asthma,atherosclerosis, diabetic nephropathy, glomerulonephritis, inflammatorybowel disease, Crohn's disease, multiple sclerosis, pancreatitis,pulmonary fibrosis, psoriasis, restenosis, rheumatoid arthritis, andtransplant rejection, or a chronic or acute immune disorder, or acombination of any of these disease conditions.

Methods of Use

A fourth embodiment of the present invention provides a method fortreating a disease treatable by administration of an MCP-1 inhibitor,for example, chronic or acute inflammatory disease such as asthma,atherosclerosis, diabetic nephropathy, glomerulonephritis, inflammatorybowel disease, Crohn's disease, multiple sclerosis, pancreatitis,pulmonary fibrosis, psoriasis, restenosis, rheumatoid arthritis, or achronic or acute immune disorder, or a transplant rejection in mammalsin need thereof, comprising the administration to such mammal of atherapeutically effective amount of at least one compound of Formula I,Formula Ia, Formula II, Formula IIa, Formula III, Formula IIIa, or apharmaceutically acceptable salt or ester thereof.

The compounds of the present invention inhibit chemotaxis of a humanmonocytic cell line (THP-1 cells) induced by human MCP-1 in vitro. Thisinhibitory effect has also been observed in vivo. The compounds havebeen shown to reduce monocyte infiltration in a thioglycollate-inducedinflammation model in mice.

The compounds of the present invention have been found to prevent theonset or ameliorate symptoms in several animal models of inflammation.For example, the compounds inhibited the infiltration of ED-1 positivecells into the glomeruli and reduced the amount of urinary proteinexcretion in an anti-Thy-1 antibody-induced model of nephritis.

The ability of the compounds of this invention to block the migration ofmonocytes and prevent or ameliorate inflammation, which is demonstratedin the specific examples, indicates their usefulness in the treatmentand management of disease states associated with aberrant leukocyterecruitment.

The use of the compounds of the invention for treating inflammatory andautoimmune disease by combination therapy may also comprise theadministration of the compound of the invention to a mammal incombination with common anti-inflammatory drugs, cytokines, orimmunomodulators.

The compounds of this invention are thus used to inhibit leukocytemigration in patients which require such treatment. The method oftreatment comprises the administration, orally or parenterally, of aneffective quantity of the chosen compound of the invention, preferablydispersed in a pharmaceutical carrier. Dosage units of the activeingredient are generally selected from the range of 0.01 to 1000 mg/kg,preferably 0.01 to 100 mg/kg, and more preferably 0.1 to 50 mg/kg, butthe range will be readily determined by one skilled in the art dependingon the route of administration, age, and condition of the patient. Thesedosage units may be administered one to ten times daily for acute orchronic disease. No unacceptable toxicological effects are expected whencompounds of the invention are used in accordance with the presentinvention.

The invention compounds maybe administered by any route suitable to thesubject being treated and the nature of the subject's condition. Routesof administration include, but are not limited to, administration byinjection, including intravenous, intraperitoneal, intramuscular, andsubcutaneous injection, by transmucosal or transdermal delivery, throughtopical applications, nasal spray, suppository and the like, or may beadministered orally. Formulations may optionally be liposomalformulations, emulsions, formulations designed to administer the drugacross mucosal membranes or transdermal formulations. Suitableformulations for each of these methods of administration may be foundin, for example, “Remington: The Science and Practice of Pharmacy”, A.Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins,Philadelphia, Pa.

EXAMPLES

The following Examples serve to illustrate the preparation, properties,and therapeutic applications of the compounds of this invention. TheseExamples are not intended to limit the scope of this invention, butrather to show how to prepare and use the compounds of this invention.

Preparation of the Compounds of the Invention: General Procedures

The following general procedures may be employed for the preparation ofthe compounds of the present invention.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as the AldrichChemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma(St. Louis, Mo.), or are prepared by methods well known to a person ofordinary skill in the art, following procedures described in suchreferences as Fieser and Fieser's Reagents for Organic Synthesis, vols.1–17, John Wiley and Sons, New York, N.Y., 1991; Rodd's Chemistry ofCarbon Compounds, vols. 1–5 and supps., Elsevier Science Publishers,1989; Organic Reactions, vols. 1–40, John Wiley and Sons, New York,N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed., John Wileyand Sons, New York, N.Y.; and Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

In some cases, protective groups may be introduced and finally removed.For example, suitable protective groups for amino, hydroxy, and carboxygroups are described in Greene et al., Protective Groups in OrganicSynthesis, Second Edition, John Wiley and Sons, New York, 1991.Activation of carboxylic acids can be achieved by using a number ofdifferent reagents as described in Larock: Comprehensive OrganicTransformation, VCH Publishers, New York, 1989.

The starting materials, intermediates, and compounds of this inventionmaybe isolated and purified using conventional techniques, includingprecipitation, filtration, distillation, crystallization,chromatography, and the like. The compounds may be characterized usingconventional methods, including physical constants and spectroscopicmethods.

Generally, a compound of Formula I, Formula II, or Formula III:

where n, W, X, Y, Z, and R¹–R⁵ are as defined in the first embodiment,may be prepared by a process comprising:

(a) contacting a compound of Formula Ib, Formula IIb, or Formula IIIb:

with a compound of the formula R⁵—N═C═O under conditions sufficient toproduce a compound of Formula I, Formula II, or Formula III, where R³and R⁴ are both H; or

(b) optionally, contacting a compound of Formula Ic, Formula IIc, orFormula IIIc:

where X is halogen, nitro, —CN, or —OR⁹, with a compound of the formulaR¹—H under conditions sufficient to produce a compound of Formula I,Formula II, or Formula III; or

-   (c) contacting a compound of Formula Ib, Formula IIb, or Formula    IIIb:    with a haloformylation reagent and a compound of the formula R⁴R⁵NH    under conditions sufficient to produce a compound of Formula I,    Formula II, or Formula III, where R⁴ is H; or-   (d) elaborating substituents of a compound of Formula I, Formula II,    or Formula III in a manner known per se, or-   (e) reacting the free base of a compound of Formula I, Formula II,    or Formula III with an acid to give a pharmaceutically acceptable    addition salt; or-   (f) reacting an acid addition salt of a compound of Formula I,    Formula II, or Formula III with a base to form the corresponding    free base; or-   (g) converting a salt of a compound of Formula I, Formula II, or    Formula III to another pharmaceutically acceptable salt of a    compound of Formula I, Formula II, or Formula III; or-   (h) resolving a racemic mixture of any proportions of a compound of    Formula I, Formula II, or Formula III to yield a stereoisomer    thereof.

Step (a), above, may be carried out in the presence of an organicsolvent or a mixture of solvents at elevated temperatures. Said organicsolvent may be toluene, and the reaction may be carried out underrefluxing conditions.

Step (b), above, may be carried out using the salt of the compound ofthe Formula R¹—H in an inorganic solvent. Said salt may be the lithium,sodium, or potassium salt.

Step (c), above, may be carried out in an organic solvent or a mixtureof solvents at elevated temperatures. The haloformylation reagent may bea compound of the formula A-(CO)-B where A and B are, independently,suitable leaving groups such as halogens, —COCl, —COBr and the like. Thehaloformylation agent and organic solvent employed in step (c) may beoxalyl chloride and THF, respectively, and the ensuing reaction may beheated to above 50° C.

The compounds of the invention can further be synthesized as shown inthe following examples. These examples are merely illustrative of somemethods by which the compounds of this invention can be synthesized, andvarious modifications to these examples can be made and will besuggested to a person of ordinary skill in the art having regard to thisdisclosure.

Acylurea compounds of the present invention may be prepared startingwith an aryl carboxamide and an isocyanate. Carboxamide and isocyanatestarting materials may be purchased from various different commercialsources, such as, for example the Aldrich Chemical Company, supra, orthey may be prepared from standard procedures known in the art forpreparing these compounds, such as the procedures described in theabove-cited references. The isocyanates may also be prepared accordingto the procedures described in the example below. Typically, an arylcarboxamide is treated with an aryl isocyanate in an organic solvent ormixtures of suitable organic solvents. Preferably, the organic solventis toluene. The carboxamide and the isocyanate may be combined assolutions or suspensions, depending on the solubilities of the compoundsin the selected solvent. The carboxamide and the isocyanate maybe addedin a stoichiometric ratio (1:1), or a slight excess of the isocyanatemaybe used, for example between 1.01 fold and 2 fold excess, buttypically about 1.01 to about 1.2 fold excess. Typically, the isocyanateis added to a suspension of the carboxamide in toluene, and theresulting mixture is heated until the reaction is determined to becomplete. The reaction mixture may be heated at about 10° C. to about150° C., preferably at about 40° C. to about 120° C. under an inertatmosphere such as nitrogen, or the reaction mixture may be maintainedat the refluxing temperature of the mixture. The reaction may be allowedto proceed to completion in about 10 minutes to 24 hours. Preferably,the reaction is heated to reflux until the reaction is complete, overabout 6 to 24 hours.

Upon cooling of the reaction mixture, the resulting precipitatedacylureas may be isolated by conventional techniques. Typically, theproduct is isolated by filtration. The precipitated solid may befiltered, washed with a solvent or a series of solvents, and isolatedwithout further purification. Preferably, the precipitated acylureas maybe washed with a combination of toluene, methanol and then with ether,and the product may be dried under vacuum. If desired, the acylureas maybe further purified using conventional techniques, such as bycrystallization using conventional methods known in the art. Optionally,acylureas prepared according to this procedure may be converted to thecorresponding salts prior to isolation and/or purification, or aftercrystallization.

Acylureas may also be prepared from the condensation of an arylcarboxamide with an amine. The carboxamide may be prepared from thecorresponding carboxylic acid or may be obtained from commercialsources. Depending on the desired substitution of the amine, optionally,the amine may be substituted where one substituted group is an amineprotecting group such that the protecting group may be removed in asubsequent step if desired. In the first step of the process, acarboxamide mixture in a suitable aprotic solvent is treated with ahaloformylation reagent to form the corresponding carboxamidecarbonylchloride derivative. Typically, the aprotic solvent isdichloromethane, toluene, 2-methyltetrahydrofuran or THF, and thehaloformylation reagent is oxalyl chloride. Preferably, the aproticsolvent is THF. Oxalyl chloride is preferably present in an excess, forexample between 1.1 to 3.0 equivalents, typically about 1.5 equivalentover the carboxamide. The reaction is generally performed under an inertatmosphere where the mixture is heated to 50° C. to 175° C. for 15minutes to 24 hours until the reaction is deemed complete. Typically,the reaction is heated to reflux over 2 to 16 hours under nitrogen, andthen cooled to room temperature. The solvent is removed in vacuo byrotoevaporation or distillation, and the resulting carboxamidecarbonylchloride is then condensed with a primary or secondary amine.Condensation with the amine may be performed by the addition of asolution of the amine in an aprotic solvent, such as THF, under an inertatmosphere, at a temperature between 0° C. and 20° C., preferablybetween 0° C. and 5° C. If the chloroformylation and the subsequentcondensation reaction is performed in the same solvent, the solventremoval step may be eliminated. Preferably, the reaction is performed at0° C. to 5° C. for 1 to 24 hours, until the reaction is complete. Thesolvent is removed by concentration under reduced pressure, and theacylurea can be isolated by conventional techniques such as filtrationand washing of the crude product with a solvent, followed by dryingunder vacuum.

The preparation of the acylureas may also be performed starting with anamine or aniline derivative through a condensation reaction with aphosgene equivalent, followed by a condensation reaction with thecarboxamide. Typically, a solution of an aniline or aniline derivativeand triphosgene in tetrachloroethane or other suitable organic solventis combined and stirred at 25° C. to 80° C. under an inert atmospherefor 2 to 12 hours until the reaction is complete. The solvent is removedunder reduced pressure and the residue is dissolved in an aproticsolvent, such as toluene, and the resulting mixture is treated with acarboxamide. The mixture is heated to about 50° C. to 150° C.,preferably from about 75° C. to 115° C. Preferably, the reaction mixtureis heated to reflux for 2 to 24 hours until the reaction is complete,and allowed to cool to room temperature. The precipitated solid isisolated by conventional techniques such as filtration. The filteredsolid is then washed with a suitable solvent or mixtures of solvents.Typically, the solid is washed with toluene, methanol and then ether,and the washed product is dried in vacuo to give the correspondingacylurea.

Procedure D

Amino or oxy-substituted aryl acyl ureas of the present invention may beprepared starting from the corresponding aryl halide acyl urea by thereaction of the aryl halide with an amine or alcohol. Preferably, thearyl halide is an aryl chloride, which can be prepared from one or moreof the above described procedures or from standard procedures known inthe art for preparing these compounds. Typically, the acyl urea isdissolved in an organic solvent or a mixture of suitable organicsolvents. Preferably, the organic solvent is tetrahydrofuran. The acylurea and the amine or the alcohol may be combined as solutions orsuspensions, depending on the solubilities of the compounds in theselected solvent or solvent mixtures.

The acyl urea and the amine or alcohol maybe added in a stoichiometricratio (1:1), or a slight excess of the amine or alcohol maybe used, forexample, between 1.01 fold and 20 fold excess, but typically about 1.01to about 10 fold excess. Typically, the amine or alcohol is added to theacyl urea in tetrahydrofuran and the resulting mixture is stirred atabout 0° C. to refluxing temperatures of the solvent, preferably atabout 10° C. to about 50° C. most preferably at about room temperaturesunder an inert atmosphere such as nitrogen. The reaction mixture ismaintained at the reaction temperature until the reaction proceeds tocompletion. The reaction may be allowed to proceed to completion inabout 10 minutes to 48 hours. Preferably, the reaction is stirred atroom temperature for about 5 hours. When the reaction is deemedcomplete, the resulting product may be isolated by conventionaltechniques. Typically, the solvent and excess amine or alcohol may beremoved by evaporation under reduced pressure, and the residue issuspended in a solvent. Preferably, the solvent is water. The suspensionor solid may be filtered and washed with water or a suitable solvent,and then isolated and dried using conventional methods.

Procedure E

Cyclic acyl ureas of the present invention may be prepared according tomethods known in the art. One method comprises the alkylation of theacyl urea nitrogens with an alkylating agent generically representedabove as X—(CH₂)₂₋₄—Y, where X and Y are leaving groups, and may be thesame or different. Leaving groups known in the art include halides,methanesulfonates, trifluoromethanesulfonates, p-toluenesulfonates,p-bromotoluenesulfonate, p-nitrobenzenesulfonates and the like.Representative alkylating agents include 1,2-dibromoethane,1,3-dibromoethane, 1,3-dibromopropane, and the corresponding sulfonatesand mixed halosulfonates.

Typically, the acyl urea is treated with a base in an organic solvent ormixtures of solvents. Preferably, the base is an inorganic base such assodium hydride, or an organic base such as dimethyl sulfoxide and sodiumhydride. Preferably, the solvent is a polar, aprotic solvent such astetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glycols, ormixtures of such solvents. Typically, a solution or suspension of theacyl urea is slowly added to the base in an organic solvent at about 0°C. to about 25° C. and the resulting mixture is stirred for about 10minutes to about 5 hours, preferably about 30 minutes. The alkylatingagent is added and the mixture is stirred until the reaction is deemedcomplete. Alkylation of both urea nitrogens may be accomplished in asingle step, or may be accomplished sequentially in a two step procedurebe exposing the partially alkylated product with the same or differentbase. The reaction is then quenched with a solvent, preferably water,and the mixture is extracted multiple times with an organic solvent.Preferably, the extracting solvent is dichloromethane. The combinedorganic extracts are washed with water, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to afford the product,which may be purified using standard conditions known in the art.Purification may be performed by silica gel chromatography in a mixtureof organic solvents, such as ethyl acetate and petroleum ether.

Example 12H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide(6)

Piperonyloyl chloride (3.02 g) was cooled in an ice bath and treatedwith 28–30% aqueous ammonia (30 mL). The ice bath was removed and themixture stirred at room temperature for 1 h. The solid was collected byfiltration, washed with water and dried under high vacuum to yield2H-benzo[d]1,3-dioxolane-5-carboxamide. A portion of this material (0.40g) was suspended in anhydrous dichloromethane (6 mL) under a nitrogenatmosphere and treated with oxalyl chloride (1.8 mL of a 2M solution indichloromethane). The mixture was heated at gentle reflux for 16 h andthen cooled to room temperature. The solvent was removed under reducedpressure and the residue dissolved in anhydrous tetrahydrofuran (7.5mL). An aliquot of this solution (2.5 mL) was added to an ice-cooled,stirred solution of 3-chloroaniline (85 μL) in anhydrous tetrahydrofuran(1 mL). The ice-bath was removed and the mixture stirred at roomtemperature for 2 h. The precipitated solid was collected by filtration,washed with dichloromethane, and dried under high vacuum to give thetitle compound.

¹H NMR (DMSO-d₆) δ 6.16 (s, 2H), 7.06 (d, 1H, J=8.2 Hz), 7.15 (d, 1H,J=7.8 Hz), 7.35 (t, 1H, J=8.0 Hz), 7.44 (d, 1H, J=8.3 Hz), 7.59 (d, 1H,J=1.6 Hz), 7.67 (d, 1H, J=8.2 Hz), 7.83 (d, 1H, J=2.0 Hz), 10.93 (s, 1H,10.95 (s, 1H). MS (ESI) m/z 317, 319.

Example 2N-({[3,5-bis(Trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-6-yl)carboxamide(98)

Sodium hydride (0.77 g of a 60% suspension in mineral oil) was washedwith anhydrous hexane (2×10 mL) under a nitrogen atmosphere and thensuspended in anhydrous N,N-dimethylformamide (DMF, 30 mL). A solution ofindole-6-carboxylic acid (1.01 g) in DMF (20 mL) was added over 5 minand the solution stirred at room temperature for an additional 30 min.Iodomethane (1.2 mL) was added and the mixture stirred for 1 h. Thesolution was poured onto ice and allowed to warm up to room temperature.The resulting solid was collected by filtration, washed with water anddried under high vacuum to afford methyl 1-methylindole-6-carboxylate. Apotion of this material (0.33 g) was dissolved in methanol (7 mL) andDMF (1 mL) and treated with 5N aqueous sodium hydroxide solution (2 mL).The mixture was heated at reflux for 22 h and then allowed to cool toambient temperature. The solvent was evaporated under reduced pressure.The residue was dissolved in water (15 mL) and the solution was cooledin an ice-bath and acidified to pH 4 with concentrated HCl. Theprecipitated solid was collected by filtration, washed with water anddried under high vacuum to produce 1-methylindole-6-carboxylic acid. Aportion of this material (0.27 g) was dissolved in DMF (4 mL), andtreated with diisopropylethylamine (1.6 mL) and ammonia (12 mL of a 0.5Msolution in dioxane) under a nitrogen atmosphere. O-Benzotriazol-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.64 g) was added and themixture stirred at room temperature for 20 h. The solvent was removedunder reduced pressure. The residue was dissolved in ethyl acetate (50mL), and the solution washed with water, 1M sodium carbonate solution,and brine, and dried over magnesium sulfate. Evaporation of the solventunder reduced pressure produced 1-methylindole-6-carboxamide as anoff-white solid. A portion of this material (0.04 g) was suspended inanhydrous toluene (1.0 mL) under a nitrogen atmosphere, and treated with3,5-bis(trifluoromethylphenyl isocyanate (42 μL). The mixture was heatedat reflux for 2 h and then allowed to cool to room temperature. Thesolid was collected by filtration, washed with petroleum ether,dichloromethane and methanol and dried under high vacuum to yield thetitle compound.

¹H NMR (DMSO-d₆) δ 3.91 (s, 3H), 6.55 (d, 1H, J=2.9 Hz), 7.62 (d, 1H,J=3.0 Hz), 7.67 (d, 1H, J=8.4 Hz), 7.73 (d, 1H, J=8.4 Hz), 7.82 (s, 1H),8.40 (br. s, 3H), 11.14)br. s, 1H), 11.44 (s, 1H). MS (ESI) m/z 428.

Example 3 Benzoxazol-6-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide(83)

A solution of 4-amino-3-hydroxybenzoic acid (10.0 g) in 85% formic acid(60 mL) was heated at reflux for 3 h and then cooled to roomtemperature. The precipitated solid was filtered, washed with methanol,and dried under vacuum to produce 4-carbonylamino-3-hydroxybenzoic acid.A portion of this material (1.00 g) and zinc chloride (3.76 g) weresuspended in m-xylene (135 L), and treated with 2 drops of concentratedsulfuric acid. The reaction mixture was azeotroped for 8 h, cooled toroom temperature, and treated with water (20 mL). The resulting solidwas collected by filtration, washed with water, and dried under highvacuum to afford benzoxazole-6-carboxylic acid. A portion of thismaterial (0.80 g) was suspended in anhydrous dichloromethane (30 mL)under a nitrogen atmosphere and treated with oxalyl chloride (12.3 mL ofa 2M solution in dichloromethane) and 1 drop of DMF. This suspension wasstirred at room temperature for 16 h. The solvent was evaporated underreduced pressure. The residue was suspended in dichloromethane (20 mL)and poured into an ice-cold 2M solution of ammonia in methanol (122 mL).The mixture was stirred at 0° C. for 1 h, and concentrated under reducedpressure. The solid residue was washed with dichloromethane and water,and dried under high vacuum to afford benzoxazole-6-carboxamide. Aportion of this material (80 mg) was dried by azeotropic distillationwith toluene (5.3 mL) and treated with 3-chlorophenyl isocyanate (83.3mg). The mixture was heated at reflux for 6 h, allowed to cool to roomtemperature, and treated with methanol (5 mL). The precipitated solidwas collected by filtration, washed with methanol and dichloromethane,and dried under high vacuum to yield the title compound. ¹H NMR(DMSO-d₆) δ 7.18 (d, 1H, J=8.0 Hz), 7.39 (t, 1H, J=8.0 Hz), 7.49 (d, 1H,J=8.0 Hz), 7.86 (d, 1H, J=1.6 Hz), 7.97 (d, 1H, J=8.4 Hz), 8.09 (dd, 1H,J=8.4, 1.6 Hz), 8.50 (s, 1H), 8.98 (s, 1H), 10.90 (s, 1H), 11.24 (s,1H). MS (ESI) m/z 314, 316.

Compounds of General Formulae Ia, IIa, and IIIa

The compounds shown in Tables 1 to 11 were prepared either by theprocedures described above or by modifications of these proceduresfamiliar to those skilled in the art.

TABLE 1

MS Cmpd # R¹ R² R³ R⁴ R⁵ MW (m/z) 1 H Cl OH H H 334.71 333 2 H Cl Cl H H353.16 351, 353 3 i-Pr H H H i-Pr 368.43 367 4 H H OH H H 300.28 299 5 HCl OMe H H 348.74 347 6 H Cl H H H 318.71 317 7 H H H H H 284.27 283 8OH H H Cl H 334.71 333, 335 9 H F H H H 302.26 301 10 F H H H F 320.25319 11 F F H H H 320.25 319 12 H H F H H 302.26 301 13 H H Cl H H 318.71317 14 H F F H H 320.25 319 15 H H CF₃ H H 352.27 371 16 H CF₃ H H H352.27 351 17 H H NO₂ H H 329.27 328 18 H CF₃ NO₂ H H 397.26 396 19 HCF₃ Cl H H 386.71 385, 387 20 H H Br H H 363.17 361, 363 21 H Br H H H363.17 361, 363 22 H CN H H H 309.30 308 23 Cl H Cl H H 353.16 351, 35324 H H OMe H H 314.30 313 25 H H I H H 410.17 409 26 H I H H H 410.17409 27 H H CONH₂ H H 327.29 327 28 H F CF₃ H H 370.26 369 29 H CF₃ F H H370.26 369 30 H H Ph H H 360.37 359 31 H OCF₃ H H H 368.27 367 32 H SCF₃H H H 384.33 383 33 H CF₃ H CF₃ H 420.26 419 34 H i-Pr H H H 360.37 36035 H Et H H H 312.32 311 36 H OEt H H H 328.32 327 37 H Oi-Pr H H H342.35 341 38 H t-Bu H H H 340.38 339 39 H Ph H H H 360.37 359 40 H ClMe H H 332.74 331, 333 41 H I Me H H 424.19 423 42 H CF₃ Me H H 366.29365 43 H OPh H H H 376.37 375 44 H NO₂ H H H 329.27 328 45 H Cl H Cl H353.16 351, 353 46 H Ac H H H 326.30 325 47 H CO₂Me H H H 342.31 341 48H 1H-1,2,3,4- H H H 325.31 351 tetrazol-5-yl 49 H ethynyl H H H 308.29307 50 Me Cl H H H 332.74 351 51 Me H H Cl H 332.74 331 52 Et Cl H H Et374.82 373 53 Me H H I H 424.19 423 54 H 2-pyridyl H H H 361.36 362 55 H1,3-thiazol-2-yl H H H 367.38 368 56 H 3-thienyl H H H 366.40 365 57 H2-furyl H H H 350.33 349 58 H 2-thienyl H H H 366.40 365

TABLE 2

Cmpd # R MW MS(m/z) 59 3,4-Methylenedioxyphenyl 328.28 327 605-Trifluoromethyl-1,2,3-thiadiazol-2-yl 360.27 359 615-Chloro-1,3-thiazol-2-yl 325.73 324, 326 626-Chloro-4-methylpyrimidin-2-yl 334.72 333, 335 63 2-Chloro-4-pyridyl319.70 318, 320

TABLE 3

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 64 H CN H H H 343.73 342 65 H I H H H444.61 443 66 H CF₃ H H H 386.71 385 67 H Oi-Pr H H H 376.79 375 68 HCF₃ F H H 404.70 403

TABLE 4

Cmpd # R¹ R² MW MS(m/z) 69 Me Me 346.77 347, 349 70 Me H 332.74 ND

TABLE 5

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 71 H Cl Cl H H 350.16 348, 350 72 H HCl H H 315.72 314 73 H Cl H H H 315.72 314 73 H Br H H H 360.17 358, 36075 H H CF₃ H H 349.27 348 76 H I H H H 407.16 406 77 H CF₃ H H H 349.27348 78 H CF₃ H CF₃ H 417.26 418 79 H H F H H 299.26 298

TABLE 6

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 80 H Cl Cl H H 350.16 348, 350 81 H HCl H H 315.72 314 82 H H CF₃ H H 349.27 348 83 H Cl H H H 315.72 314 84H CF₃ H H H 349.27 348 85 H CF₃ H CF₃ H 417.26 417 86 H OCF₃ H H H365.27 364 87 H CN H H H 306.28 305 88 H CF₃ F H H 367.26 366 89 H Br HH H 360.17 358 90 H CO₂CH₃ H H H 339.30 338 91 H Cl CO₂H H H 359.72 35892 H Cl OCH₂CO₂- H H 479.87 478 CH₂Ph 93 H H CO₂H H H 325.27 324 94 HCO₂H Cl H H 359.72 358 95 H Cl CO₂Na H H 381.70 358 96 H CO₂Na Cl H H381.70 358 97 H H CO₂Na H H 347.25 ND

TABLE 7

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 98 H CF₃ H CF₃ H 429.32 428 99 H CF₃ HH H 361.32 360 100 H Cl Cl H H 362.21 360, 362, 364 101 H I H H H 419.22418 102 H CN H H H 318.33 317 103 H CF₃ F H H 379.31 378

TABLE 8

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 104 H Cl Cl H H 362.21 360, 362, 364105 H Cl H H H 327.77 326, 328 106 H Br H H H 372.22 370, 372 107 H CF₃H CF₃ H 429.32 428 108 H CF₃ F H H 379.31 378

TABLE 9

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 109 H Cl Cl H H 350.16 348, 350 110 H HCl H H 315.72 314

TABLE 10

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 111 H Cl Cl H H 351.19 349, 351, 353112 H Cl H H H 316.74 315, 317 113 H H CF₃ H H 350.29 349 114 H H F H H300.29 299 115 H H OMe H H 312.32 311

TABLE 11

Cmpd # R¹ R² R³ R⁴ R⁵ Form MW MS(m/z) 116 H Cl Cl H H Free base 363.20361, 363 117 H Cl Cl H H HCl salt 399.66 361, 363

The names of the compounds shown in Tables 1 to 11 are given in Table12. These names were generated with the Chemistry 4-D Draw™ softwarefrom ChemInnovation Software, Inc. (San Diego, Calif.).

TABLE 12 Cmpd # IUPAC Name 12H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-chloro-4-hydroxyphenyl)amino]carbonyl}carboxamide22H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide32H-Benzo[d]1,3-dioxolan-5-yl-N-({[2,6-bis(methylethyl)phenyl]amino}carbonyl)carboxamide42H-Benzo[d]1,3-dioxolan-5-yl-N-{[(4-hydroxyphenyl)amino]carbonyl}carboxamide52H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-chloro-4-methoxyphenyl)amino]carbonyl}carboxamide62H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide7 2H-Benzo[d]1,3-dioxolan-5-yl-N-[(phenylamino)carbonyl]carboxamide 82H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(5-chloro-2-hydroxyphenyl)amino]carbonyl}-carboxamide 92H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-fluorophenyl)amino]carbonyl}carboxamide102H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(2,6-difluorophenyl)amino]carbonyl}carboxamide112H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(2,3-difluorophenyl)amino]carbonyl}carboxamide122H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-fluorophenyl)amino]carbonyl}carboxamide132H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide142H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3,4-difluorophenyl)amino]carbonyl}carboxamide152H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)-carboxamide 162H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)-carboxamide 172H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-nitrophenyl)amino]carbonyl}carboxamide182H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[4-nitro-3-(trifluoromethyl)phenyl]amino}carbonyl)-carboxamide 192H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-carboxamide 202H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-bromophenyl)amino]carbonyl}carboxamide212H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-bromophenyl)amino]carbonyl}carboxamide222H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-cyanophenyl)amino]carbonyl}carboxamide232H-Benzo[d]1,3-dioxolan-5-yl-N-{[(2,4-dichlorophenyl)amino]carbonyl}carboxamide242H-Benzo[d]1,3-dioxolan-5-yl-N-{[(4-methoxyphenyl)amino]carbonyl}carboxamide252H-Benzo[d]1,3-dioxolan-5-yl-N-{[(4-iodophenyl)amino]carbonyl}carboxamide262H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-iodopheny)amino]carbonyl}carboxamide274-{[(2H-Benzo[d]1,3-dioxolan-5-ylcarbonylamino)carbonyl]amino}benzamide282H-Benzo[d]1,3-dioxolan-5-yl-N-({[3-fluoro-4-(trifluoromethyl)phenyl]amino}carbonyl)-carboxamide 292H-Benzo[d]1,3-dioxolan-5-yl-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-carboxamide 302H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-phenylphenyl)amino]carbonyl}carboxamide312H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(trifluoromethoxy)phenyl]amino}carbonyl)-carboxamide 322H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(trifluoromethylthio)phenyl]amino}carbonyl)-carboxamide 332H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)-carboxamide 342H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(methylethyl)phenyl]amino}carbonyl)carboxamide352H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-ethylphenyl)amino]carbonyl}carboxamide362H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-ethoxyphenyl)amino]carbonyl}carboxamide372H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(methylethoxy)phenyl]amino}carbonyl)carboxamide382H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(tert-butyl)phenyl]amino}carbonyl)carboxamide392H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-phenylphenyl)amino]carbonyl}carboxamide402H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-chloro-4-methylphenyl)amino]carbonyl}carboxamide412H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-iodo-4-methylphenyl)amino]carbonyl}carboxamide422H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[4-methyl-3-(trifluoromethyl)phenyl]amino}carbonyl)-carboxamide 432H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-phenoxyphenyl)amino]carbonyl}carboxamide442H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-nitrophenyl)amino]carbonyl}carboxamide452H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3,5-dichlorophenyl)amino]carbonyl}carboxamide462H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-acetylphenyl)amino]carbonyl}carboxamide47 Methyl3-{[(2H-Benzo[3,4-d]1,3-dioxolen-5-ylcarbonylamino)carbonyl]amino}benzoate482H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(1H-1,2,3,4-tetraazol-5-yl)phenyl)amino]carbonyl}-carboxamide 492H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-ethynylphenyl)amino]carbonyl}carboxamide502H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-chloro-2-methylphenyl)amino]carbonyl}carboxamide512H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(5-chloro-2-methylphenyl)amino]carbonyl}carboxamide522H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-chloro-2,6-diethylphenyl)amino]carbonyl}-carboxamide 532H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(5-iodo-2-methylphenyl)amino]carbonyl}carboxamide542H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(2-pyridyl)phenyl)amino]carbonyl}carboxamide552H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(1,3-thiazol-2-yl)phenyl)amino]carbonyl}-carboxamide 562H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(3-thienyl)phenyl)amino]carbonyl}carboxamide572H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(2-furyl)phenyl)amino]carbonyl}carboxamide582H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(2-thienyl)phenyl)amino]carbonyl}carboxamide592H-Benzo[d]1,3-dioxolan-5-yl-N-[(2H-Benzo[3,4-d]1,3-dioxolen-5-ylamino)carbonyl]-carboxamide 602H-Benzo[d]1,3-dioxolan-5-yl-N-({[5-(trifluoromethyl)(1,3,4-thiadiazol-2-yl)]amino}carbonyl)-carboxamide 612H-Benzo[d]1,3-dioxolan-5-yl-N-{[(5-chloro(1,3-thiazol-2-yl))amino]carbonyl}carboxamide622H-Benzo[d]1,3-dioxolan-5-yl-N-{[(6-chloro-4-methylpyrimidin-2-yl)amino]carbonyl}-carboxamide 632H-Benzo[d]1,3-dioxolan-5-yl-N-{[(2-chloro(4-pyridyl))amino]carbonyl}carboxamide64(6-Chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-{[(3-cyanophenyl)amino]carbonyl}-carboxamide 65(6-Chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-{[(3-iodophenyl)amino]carbonyl}carboxamide66(6-Chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-({[3-(trifluoromethyl)phenyl]amino}-carbonyl)carboxamide 67(6-Chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-({[3-(methylethoxy)phenyl]amino}carbonyl)-carboxamide 68(6-Chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}-carbonyl)carboxamide 692H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-chlorophenyl)methylamino]carbonyl}-N-methyl-carboxamide 702H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}-N-methylcarboxamide71 Benzoxazol-5-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide 72Benzoxazol-5-yl-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide 73Benzoxazol-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide 74Benzoxazol-5-yl-N-{[(3-bromophenyl)amino]carbonyl}carboxamide 75Benzoxazol-5-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide76 Benzoxazol-5-yl-N-{[(3-iodophenyl)amino]carbonyl}carboxamide 77Benzoxazol-5-yl-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide78Benzoxazol-5-yl-N-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)carboxamide79 Benzoxazol-5-yl-N-{[(4-fluorophenyl)amino]carbonyl}carboxamide 80Benzoxazol-6-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide 81Benzoxazol-6-yl-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide 82Benzoxazol-6-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide83 Benzoxazol-6-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide 84Benzoxazol-6-yl-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide85Benzoxazol-6-yl-N-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)carboxamide86Benzoxazol-6-yl-N-({[3-(trifluoromethoxy)phenyl]amino}carbonyl)carboxamide87 Benzoxazol-6-yl-N-{[(3-cyanophenyl)amino]carbonyl}carboxamide 88Benzoxazol-6-yl-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide89 Benzoxazol-6-yl-N-{[(3-bromophenyl)amino]carbonyl}carboxamide 90Methyl 3-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}benzoate 914-{[(Benzoxazol-6-ylcarbonylamino)carbonyl]amino}-2-chlorobenzoic acid92 Phenylmethyl2-(4-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}-2-chlorophenoxy)acetate93 4-{[(Benzoxazol-6-ylcarbonylamino)carbonyl]amino}benzoic acid 945-{[(Benzoxazol-6-ylcarbonylamino)carbonyl]amino}-2-chlorobenzoic acid95 Sodium4-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}-2-chlorobenzoate 96Sodium5-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}-2-chlorobenzoate 97Sodium 4-{[(benzoxazol-6-ylcarbonylamino)carbonyl]aniino}benzoate 98N-({[3,5-bis(Trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-6-yl)carboxamide99(1-Methylindol-6-yl)-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide100N-{[(3,4-Dichloropheny)amino]carbonyl}(1-methylindol-6-yl)carboxamide101 N-{[(3-Iodophenyl)amino]carbonyl}(1-methylindol-6-yl)carboxamide 102N-{[(3-Cyanophenyl)amino]carbonyl}(1-methylindol-6-yl)carboxamide 103N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-6-yl)carboxamide104N-{[(3,4-Dichlorophenyl)amino]carbonyl}(1-methylindol-5-yl)carboxamide105 N-{[(3-Chlorophenyl)amino]carbonyl}(1-methylindol-5-yl)carboxamide106 N-{[(3-Bromophenyl)amino]carbonyl}(1-methylindol-5-yl)carboxamide107N-({[3,5-bis(Trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-5-yl)carboxamide108N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-5-yl)carboxamide109 Benzotriazol-5-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide110 Benzotriazol-5-yl-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide 111N-{[(3,4-Dichlorophenyl)amino]carbonyl}-2,3-dihydrobenzo[b]furan-5-ylcarboxamide112N-{[(3-Chlorophenyl)amino]carbonyl}-2,3-dihydrobenzo[b]furan-5-ylcarboxamide1132,3-Dihydrobenzo[b]furan-5-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide1142,3-Dihydrobenzo[b]furan-5-yl-N-{[(4-fluorophenyl)amino]carbonyl}carboxamide1152,3-Dihydrobenzo[b]furan-5-yl-N-{[(4-methoxyphenyl)amino]carbonyl}carboxamide116N-{[(3,4-Dichlorophenyl)amino]carbonyl}(1-methylbenzimidazol-5-yl)carboxamide117N-{[(3,4-Dichlorophenyl)amino]carbonyl}(1-methylbenzimidazol-5-yl)carboxamide,hydrochloride

Example 4 Inhibition of MCP-1 Induced Chemotaxis

A 96 well microchemotaxis chamber with a 5 μm-pore size, PVP-coatedpolycarbonate filter membrane (Neuro Probe Inc., Cabin John, Md.) wasused for testing. Compounds were prepared as 10 mM stock solution inDMSO. THP-1 cells (2×10⁶ cells/mL) were Labeled with 5 μM Calcein AMcontaining 0.1% F127 (Molecular Probe, Eugene, Oreg.) at 37° C. for 30min, and then pretreated with compound at room temperature for anadditional 30 min. The lower chamber was loaded with medium containing12.5 nM hMCP-1. The filter membrane was placed over the lower chamber,followed by a silicon gasket and the upper chamber. The pretreated THP-1cells (4×10⁵ cells/50 μL of RPMI1640 medium per well) were added to theupper chamber and incubated in 5% CO₂ at 37° C. for 2 hr. The migratedcells were determined with a fluorescent plate reader (LJL BioSystems,Sunnyvale, Calif.). Table 13 shows the IC₅₀ (concentration of compoundThat inhibited migration of 50% of the cells relative to control) forseveral compounds of the present invention.

TABLE 13 Effect of Selected Compounds on MCP-1 Induced Chemotaxis Cmpd #IC₅₀ (μM) 1 4.284 2 11.833 6 4.170 13 >100 16 0.760 19 13.302 21 3.64022 3.093 23 5.904 25 11.661 26 0.198 29 29.296 31 2.175 33 0.955 370.649 39 2.699 54 0.438 55 0.203 56 0.658 57 10.158 58 3.668 65 8.051 710.857 74 3.674 75 >100 80 0.168 81 3.185 83 1.228 84 1.756 86 0.362 874.629 88 1.720 89 1.207 98 1.353 100 0.598 101 0.536 102 4.488 105 8.962111 8.181

Example 5 Thioglycollate-Induced Inflammation Model

3% Brewer's thioglycollate broth (Difco, Detroit, Mich.) was injectedinto the peritoneal cavity of ICR male mice, followed by subcutaneousadministration of the same dose of test compound after 0 h, 3 h and 16hours post-thioglycollate injection, respectively. After 96 h, thenumber of total elicited cells and MOMA2-positive cells in theperitoneal cavity was analyzed using a flowcytometer (EPICS XL, BeckmanCoulter). The results are shown in Table 14.

TABLE 14 Effect of Selected Compounds on a Thioglycollate-InducedInflammation Model Dose Total Compound (mg/kg) Cells (× 10⁶)MOMA2-positive Cells (× 10⁶) No treatment — 1.8 ± 0.3 1.7 ± 0.3 Control— 13.6 ± 1.1  11.4 ± 0.8  16 10 8.8 ± 1.5 7.5 ± 1.6 82 10 4.2 ± 0.4 3.2± 0.4 Significant difference from control group: *P < 0.05, **P < 0.01(ANOVA).

Example 6 Anti-Thy-1 Antibody Induced Nephritis Model

The efficacy of the compounds of the present invention was alsoevaluated in an animal model of nephritis. This model simulates veryclosely the conditions found in human mesangial proliferativeglomerulonephritis.

Anti-Thy-1 nephritis was induced by intravenous injection ofanti-Thy-1-antibody to male Wistar rats. The test compound wassubcutaneously administered 2 h before, immediately after, and 5 h afterthe anti-Thy-1 antibody treatment, and then twice a day for thefollowing 2 days. Anti-MCP-1 antibody was intraperitoneally injectedonce a day for 3 days. Seven days after the anti-Thy-1 antibodytreatment, the rats were sacrificed. The kidneys were perfused with 10%formaldehyde in PBS, surgically removed, and immersed in 10%formaldehyde. The kidneys were then embedded in paraffin for glomerularhistopathology or in OCT compound Miles Inc., Elkhart, Ind.) in liquidnitrogen after immersion in 30% sucrose overnight. Immunohistochemicalstaining was performed with a mouse anti-rat ED-1 monoclonal antibody.Briefly, 5 mm renal sections were prepared and endogenous peroxidaseblocked with 0.3% hydrogen peroxide. The sections were then blocked withProtein Block (DAKO, Japan) and stained with anti-ED-1 antibody for 45min. The ED-1 antigen was visualized by peroxidase-labeled anti-mouseIgG and diaminobenzidine. The amount of urinary protein was determinedwith the DC protein assay kit (Bio-Rad, Hercules, Calif.). The effect ofa representative test compound on the level of urinary protein excretionand the infiltration of ED-1 positive cells into the glomeruli is shownin Table 15.

TABLE 15 Effect of Compound 80 on Anti-Thy-1 Antibody Induced NephritisCompound Dose (mg/kg) Urinary Protein (mg/day) No treatment —  20.0 ±3.0** Control — 194.2 ± 46.7 80 1 162.1 ± 42.6 Significant differencefrom control group: **P < 0.01 (ANOVA).

Example 7 Oral Pharmaceutical Composition—Solid Dosage Formulation

A pharmaceutical composition for oral administration may be prepared bycombining the following:

% w/w Compound of this invention 10.0 Magnesium stearate 0.5 Starch 2.0(Hydroxypropyl)methylcellulose 1.0 Microcrystalline cellulose 86.5

The mixture may be compressed to tablets, or filled into hard gelatincapsules. The tablet maybe coated by applying a suspension of filmformer (e.g., (hydroxypropyl)methylcellulose), pigment (e.g., titaniumdioxide) and plasticiser (e.g., diethyl phthalate) and drying the filmby evaporation of the solvent. The film coat can comprise 2.0% to 6.0%of the tablet weight, preferably about 3.0%.

Example 8 Oral Pharmaceutical Composition Preparation—Capsule

A pharmaceutical composition of a compound of the invention suitable fororal administration may also be prepared by combining the following:

% w/w Compound of this invention 20 Polyethylene glycol 400 80

The medicinal compound is dispersed or dissolved in the liquid carrier,with a thickening agent added, if required. The formulation is thenenclosed in a soft gelatin capsule by suitable technology.

Example 9 Pharmaceutical Composition for Parenteral Administration

A pharmaceutical composition for parenteral administration may beprepared by combining the following:

Preferred Level (%) Compound of this invention 1.0 Saline 99.0

The solution is sterilized and sealed in sterile containers.

Various modifications and variations of the present invention will beapparent to those skilled in the art without departing from the scopeand spirit of the invention. Although the invention has been describedin connection with specific preferred embodiments, it should beunderstood that the invention as disclosed should not be unduly limitedto such specific embodiments. Various modifications of the describedmodes for carrying out the invention which are obvious to those skilledin the art are intended to be within the scope of this invention.

1. A compound of the formula:

where: each of W, X and Y is independently CR⁶R⁷, O, or S, provided thatat least one of W, X, and Y contains a non-carbon ring atom, and atleast one of W, X, and Y contains a carbon ring atom; Z is N or C—R⁸;each of R¹, R², R⁶, and R⁸ is independently hydrogen, optionallysubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(loweralkyl), optionally substituted heterocycloalkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedaryl(lower alkyl), halo(lower alkyl), —CF₃, halogen, nitro, —CN, —OR⁹,—SR⁹, —NR⁹R¹⁰, —NR⁹(carboxy(lower alkyl)), —C(═O)R⁹, —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —SO₂R⁹, —OSO₂R⁹, —SO₂R⁹R¹⁰, —NR⁹SO₂R¹⁰, or—NR⁹C(═O)R¹⁰, where R⁹ and R¹⁰ are independently hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl,optionally substituted cycloalkyl, cycloalkyl(lower alkyl) optionallysubstituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionallysubstituted aryl, optionally substituted heteroaryl, or heteroaryl(loweralkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆— optionally interrupted byone O, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl))or N-(optionally substituted C₁₋₂ alkyl) group; R³ and R⁴ areindependently hydrogen or lower alkyl or together are —(CH₂)₄₋₆—; eachR⁷ is independently hydrogen, optionally substituted lower alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aryl(lower alkyl),—C(═O)R⁹, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂NR⁹R¹⁰, where R⁹ andR¹⁰ are independently hydrogen, optionally substituted lower alkyl,lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl,cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(loweralkyl), aryl(lower alkyl), optionally substituted aryl, optionallysubstituted heteroaryl, or heteroaryl(lower alkyl), or R⁹ and R¹⁰together are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH,N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)), orN-(optionally substituted C₁₋₂ alkyl) group; R¹³ is hydrogen, optionallysubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(loweralkyl), heterocycloalkyl, optionally substituted aryl, optionallysubstituted aryl(lower alkyl), optionally substituted heteroaryl,optionally substituted heteroaryl(lower alkyl), halo(lower alkyl), —CF₃,halo(lower alkyl), halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶,—C(═O)R¹⁵, —C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶,—NR¹⁵SO₂R¹⁶, or —NR¹⁵C(═O)R¹⁶, where R¹⁵ and R¹⁶ are independentlyhydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, —CF₃,cycloalkyl, optionally substituted heterocycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted heteroaryl,or optionally substituted heteroaryl(lower alkyl), or together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH or N—(C₁₋₂ alkyl)group; each R¹⁴ is independently optionally substituted lower alkyl,optionally substituted aryl, optionally substituted heteroaryl, hydroxy,halogen, —CF₃, —OR¹⁷, —NR¹⁷R¹⁸, —C(═O)R¹⁷, —C(═O)OR¹⁷,O(CH₂)_(m)C(═O)OR¹⁷, where m is an integer of 1 to 4, or —C(═O)NR¹⁷R¹⁸,where R¹⁷ and R¹⁸ are independently, hydrogen, lower alkyl, alkenyl,alkynyl, —CF₃, optionally substituted heterocycloalkyl, cycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, heteroaryl,heteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆—, optionallyinterrupted by one O, S, NH or N—(C₁₋₂ alkyl) group; and n is an integerof 0 to 4; or a pharmaceutically acceptable salt thereof, as a singlestereoisomer or mixture of stereoisomers.
 2. The compound of claim 1,where W and Y are O, X is CR⁶R⁷, where R⁶ and R⁷ are independentlyhydrogen, lower alkyl, or optionally substituted aryl, and Z is C—H. 3.The compound of claim 1, where W and X are each CR⁶R⁷, where R⁶ and R⁷are independently hydrogen, lower alkyl, or optionally substituted aryl,Y is O, and Z is C—H.
 4. The compound of claim 1, where W is O, X and Yare each CR⁶R⁷, where R⁶ and R⁷ are independently hydrogen, lower alkyl,or optionally substituted aryl, and Z is C—H.
 5. The compound of claim1, where W and X are each CR⁶R⁷, where R⁶ and R⁷ are independentlyhydrogen, lower alkyl, or optionally substituted aryl, and Z is N. 6.The compound of claim 1, where W is CR⁶R⁷, where R⁶ and R⁷ areindependently hydrogen, lower alkyl, or optionally substituted aryl, Xis O, and Z is N.
 7. The compound of claim 1, where W is O, X is CR⁶R⁷,where R⁶ and R⁷ are independently hydrogen, lower alkyl, or optionallysubstituted aryl, and Z is N.
 8. The compound of claim 1, where R¹ ishydrogen, optionally substituted lower alkyl, cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aryl(lower alkyl),halogen, —OR⁹, —NR⁹[carboxy(lower alkyl)], —C(═O)OR⁹, —C(═O)NR⁹R¹⁰,—SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, where R⁹ and R¹⁰ are independentlyhydrogen, optionally substituted lower alkyl, lower alkyl-N(C₁₋₂alkyl)₂, lower alkyl(optionally substituted heterocycloalkyl),optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted aryl, optionally substituted heteroaryl, heteroaryl(loweralkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆— optionally interrupted byone O, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl))or N-(optionally substituted C₁₋₂ alkyl) group.
 9. The compound of claim1, where R² is hydrogen, optionally substituted lower alkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aryl(lower alkyl),halo(lower alkyl), halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, or —C(═O)NR⁹R¹⁰,where R⁹ and R¹⁰ are independently hydrogen, optionally substitutedlower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionallysubstituted heterocycloalkyl), optionally substituted cycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, optionallysubstituted heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ togetherare —(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-[aryl(lower alkyl)], N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.
 10. The compound of claim 1 where R³ andR⁴ are independently hydrogen or lower alkyl.
 11. The compound of claim1, where R⁶ and R⁷ are independently hydrogen, optionally substitutedlower alkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aryl(lower alkyl), —C(═O)R⁹, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰,—SO₂R⁹, or —SO₂NR⁹R¹⁰, where R⁹ and R¹⁰ are independently hydrogen,optionally substituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, alkenyl,alkynyl, optionally substituted cycloalkyl, cycloalkyl(lower alkyl),optionally substituted aryl, heteroaryl, or heteroaryl(lower alkyl). 12.The compound of claim 1, where R⁸ is hydrogen, optionally substitutedlower alkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aryl(lower alkyl), halo(lower alkyl), —CF₃, halogen, —OR⁹,—NR⁹R¹⁰, —C(═O)R⁹, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —SO₂R⁹,—SO₂NR⁹R¹⁰, —NR⁹SO₂R¹⁰ or —NR⁹C(═O)R¹⁰, where R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, optionally substituted cycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, heteroaryl,heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)),N-(carboxy(lower alkyl)) or N-(optionally substituted C₁₋₂ alkyl) group.13. The compound of claim 1, where R¹ and R² are independently hydrogen,lower alkyl, halogen, optionally lower alkyl substitutedheterocycloalkyl, —OR⁹, —SR⁹, or —NR⁹R¹⁰, where R⁹ and R¹⁰ are hydrogen,lower alkyl or optionally substituted aryl.
 14. The compound of claim 1,where R¹, R², and R⁸ are independently optionally substituted loweralkyl, cycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aryl(lower alkyl), halogen, —OR⁹, —NR⁹[carboxy(loweralkyl)], —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, where R⁹and R¹⁰ are independently, hydrogen, lower alkyl, or R⁹ and R¹⁰ togetherare —(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.
 15. The compound of claim 1, where R¹,R³, and R⁴ are hydrogen.
 16. The compound of claim 1, where R¹³ ishydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,heterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heteroaryl(lower alkyl), halo(loweralkyl), —CF₃, halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵,—C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶, or —NR¹⁵C(═O)R¹⁶, where R¹⁵ and R¹⁶ areindependently hydrogen, optionally substituted lower alkyl, alkenyl,cycloalkyl, or halo(lower alkyl).
 17. The compound of claim 1, where R¹³is alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, halogen, —CF₃, —CN, —OR¹⁵, —C(═O)R¹⁵, —C(═O)OR¹⁵, or—C(═O)NR¹⁵R¹⁶, where R¹⁵ and R¹⁶ are independently, hydrogen, loweralkyl, halo(lower alkyl), optionally substituted aryl, optionallysubstituted heteroaryl, heteroaryl(lower alkyl) or R¹⁵ and R¹⁶ togetherare —(CH₂)₄₋₆—, optionally interrupted by one O, S, NH or N—(C₁₋₂ alkyl)group.
 18. The compound of claim 1, where each R¹⁴ is independentlyoptionally substituted lower alkyl, optionally substituted aryl,optionally substituted heteroaryl, hydroxy, halogen, —CF₃, —OR¹⁷,—NR¹⁷R¹⁸, —C(═O)R¹⁷, —C(═O)OR¹⁷, —O(CH₂)_(m)C(═O)OR¹⁷, where m is aninteger of 1 to 4, or —C(═O)NR¹⁷R¹⁸, where R¹⁷ and R¹⁸ are,independently, hydrogen, lower alkyl, alkenyl, or optionally substitutedaryl.
 19. The compound of claim 1, where each R¹⁴ is independentlyhalogen, —CF_(3, —OR) ¹⁷, —C(═O)OR¹⁷, —O(CH₂)_(m)C(═O)OR¹⁷, where m isan integer of 1 to 4, or —C(═O)NR¹⁷R¹⁸, where R¹⁷ and R¹⁸ areindependently, hydrogen, lower alkyl, optionally substituted aryl,heteroaryl, or heteroaryl(lower alkyl), or R¹⁷ and R¹⁸ together are—(CH₂)₄₋₆—, optionally interrupted by one O, S, NH or N—(C₁₋₂ alkyl)group.
 20. The compound of claim 1 where R¹³ is not hydrogen and n is 1or
 2. 21. The compound of claim 20 where n is
 1. 22. The compound ofclaim 1 that is selected from:2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-chloro-4-hydroxyphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[2,6-bis(methylethyl)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(4-hydroxyphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-chloro-4-methoxyphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-[(phenylamino)carbonyl]carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(5-chloro-2-hydroxyphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-fluorophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(2,6-difluorophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(2,3-difluorophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(4-fluorophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3,4-difluorophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(4-nitrophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[4-nitro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(4-bromophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-bromophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-cyanophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(2,4-dichlorophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(4-methoxyphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(4-iodophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-iodophenyl)amino]carbonyl}carboxamide;4-{[(2H-benzo[d]1,3-dioxolan-5-ylcarbonylamino)carbonyl]amino}benzamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[3-fluoro-4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(4-phenylphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[3-(trifluoromethoxy)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[3-(trifluoromethylthio)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[3-(methylethyl)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-ethylphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-ethoxyphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[3-(methylethoxy)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[3-(tert-butyl)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-phenylphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-chloro-4-methylphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-iodo-4-methylphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[4-methyl-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-phenoxyphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-nitrophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3,5-dichlorophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-acetylphenyl)amino]carbonyl}carboxamide;methyl3-{[(2H-benzo[d]1,3-dioxolan-5-ylcarbonylamino)carbonyl]amino}benzoate;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-(1H-1,2,3,4-tetraazol-5-yl)phenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-ethynylphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-chloro-2-methylphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(5-chloro-2-methylphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-chloro-2,6-diethylphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(5-iodo-2-methylphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-(2-pyridyl)phenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-(1,3-thiazol-2-yl)phenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-(3-thienyl)phenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-(2-furyl)phenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-(2-thienyl)phenyl)amino]carbonyl}carboxamide;(6-chloro(2H-benzo[d]1,3-dioxolan-5-yl))-N-{[(3-cyanophenyl)amino]carbonyl}carboxamide;(6-chloro(2H-benzo[d]1,3-dioxolan-5-yl))-N-{[(3-iodophenyl)amino]carbonyl}carboxamide;(6-chloro(2H-benzo[d]1,3-dioxolan-5-yl))-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(6-chloro(2H-benzo[d]1,3-dioxolan-5-yl))-N-({[3-(methylethoxy)phenyl]amino}carbonyl)carboxamide;(6-chloro(2H-benzo[d]1,3-dioxolan-5-yl))-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-chlorophenyl)methylamino]carbonyl}-N-methyl-carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}-N-methylcarboxamide;N-{[(3,4-dichlorophenyl)amino]carbonyl}-2,3-dihydrobenzo[b]furan-5-ylcarboxamide;N-{[(3-chlorophenyl)amino]carbonyl}-2,3-dihydrobenzo[b]furan-5-ylcarboxamide;2,3-dihydrobenzo[b]furan-5-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;2,3-dihydrobenzo[b]furan-5-yl-N-{[(4-fluorophenyl)amino]carbonyl}carboxamide;and2,3-dihydrobenzo[b]furan-5-yl-N-{[(4-methoxyphenyl)amino]carbonyl}carboxamide;and the pharmaceutically acceptable salts thereof, as singlestereoisomers or mixtures of stereoisomers.
 23. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 and a pharmaceutically acceptable excipient.
 24. A method oftreating an allergic, inflammatory, or autoimmune disorder or diseaseselected from the group consisting of asthma, atherosclerosis,glomerulonephritis, pancreatitis, restenosis, rheumatoid arthritis,diabetic nephropathy, pulmonary fibrosis, inflammatory bowel disease,Crohn's disease, transplant rejection, and multiple sclerosis,comprising administering a therapeutically effective amount of acompound of claim 1 to a mammal in need of such treatment.